Heterocyclic derivatives

ABSTRACT

Compounds of formula (I) wherein R 1  is hydrogen or hydroxy; R 2  is hydrogen; or R 1  and R 2  are joined together so that CR 1  14 CR 2  is a double bond; X is selected from --Ch 2  CH 2  --, --C═CH--, --C.tbd.C--, --CH 2  O--, --OCH 2 , CH 2  NH--, --NHCH 2  --, --CH 2  CO--, --COCH 2  --, --CH 2  S(O) n  -- and --S(O) n  CH 2  -- (wherein n is 0, 1 or 2); Ar is phenyl which bears one or more substituents independently selected from the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di- (1-6C)alkyl!amino, carbamoyl, (1-6C) alkylcarbamoyl, di- (1-6C)alkyl!carbamoyl, (1-6C)alkenyl and oxime derivatives thereof and O--(1-6C)alkyl ethers of said oximes (1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl when substituted by one or more groups selected from (1-6C)alkoxycarbonyl, (1-6C)alkanoyl and oxime derivatives thereof and O-(1-6C)alkyl ethers of said oxime derivatives, (1-6C)alkanoylamimo, (1-6C)alkanoyloxy, (1-6C)alkanoyloxy(1-6)alkyl, carbamoyl, N-(1-6C)alkylcarbamoyl, N,N-di (1-6C)alkyl!carbamoyl, amino, (1-6C)alkylamino, di- (1-6C)alkyl!amino, (1-6C)alkoxy, (2-6C)alkenyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl (2-6C)alkenyl, (2-6C)alkynyl, phenyl, phenoxy, cyano, nitro, hydroxy and carboxy; and wherein Ar may bear further substituents; and their pharmaceutically acceptable salts inhibit squalene synthese and are hence useful in lowering cholesterol levels in blood plasma Processes for preparing compounds of formula (I) are also referred to as well as pharmaceutical compositions containing them and their use in medicine.

This application is the national phase of international applicationPCT/GB94/00910, filed Apr. 28, 1994, published as WO 94/25459 on Nov.10, 1994.

This invention concerns heterocyclic derivatives which are useful ininhibiting squalene synthase, processes for their preparation andpharmaceutical compositions containing them. The present invention isalso concerned with methods of using such heterocyclic derivatives intreating diseases and medical conditions where inhibition of squalenesynthase is desirable, for example in treating diseases or medicalconditions such as hypercholesterolemia and atherosclerosis.

Several different classes of compounds have been reported to possess thecapability of being able to lower cholesterol levels in blood plasma.For example agents which inhibit the enzyme HMG CoA reductase, which isessential for the production of cholesterol, have been reported toreduce levels of serum cholesterol. Illustrative of this class ofcompounds is the HMG CoA reductase inhibitor known as lovastatin whichis disclosed in U.S. Pat. No. 4,231,938. Other agents which are reportedto lower serum cholesterol include those which act by complexing withbile acids in the intestinal system and which are hence termed "bileacid sequestrants". It is believed that many of such agents act bysequestering bile acids within the intestinal tract. This results in alowering of the levels of bile acid circulating in the enteroheptaticsystem and promoting replacement of bile acids by synthesis in the liverfrom cholesterol, which results in an upregulation of the heptatic LDLreceptor and thus in a lowering of circulating blood cholesterol levels.

Squalene synthase (also referred to in the art as squalene synthetase)is a microsomal enzyme which catalyses the first committed step ofcholesterol biosynthesis. Two molecules of farnesyl pyrophosphate (FPP)are condensed in the presence of the reduced form of nicotinamideadenine dinucleotide phosphate (NADPH) to form squalene. The inhibitionof this committed step to cholesterol should leave unhinderedbiosynthetic pathways to ubiquinone, dolichol and isopentenyl t-RNA.Elevated cholesterol levels are known to be one of the main risk factorsfor ischaemic cardiovacsular disease. Thus, an agent which inhibitssqualene synthase should be useful in treating diseases and medicalconditions in which a reduction in the levels of cholesterol isdesirable, for example hypercholesterolemia and atherosclerosis.

Thus far, the design of squalene synthase inhibitors has concentrated onthe preparation of analogues of the substrate farnesyl pyrophosphate(FPP), and hence on compounds which contain phosphorus groups. Forexample, the preparation of phosphorous-containing squalene synthaseinhibitors is reported in published European Patent Application No.409,181; and the preparation of isoprenoid(phosphinylmethyl)phosphonates as inhibitors of squalene synthase isreported by Biller et al, J. Med. Chem., 1988, 31, 1869.

The present invention is based on the discovery that certainheterocyclic derivatives are inhibitors of squalene synthase, and arehence useful in treating diseases and medical conditions in whichinhibition of squalene synthase is desirable.

According to the present invention there is provided a compound offormula I (formula set out hereinafter together with the other chemicalformulae referred to herein), or a pharmaceutically acceptable saltthereof, wherein:

R¹ is hydrogen or hydroxy;

R² is hydrogen; or

R¹ and R² are joined together so that CR¹ -CR² is a double bond;

X is selected from --CH₂ CH₂ --, --CH═CH--, --C.tbd.C--, --CH₂ O--,--OCH₂ --, --CH₂ NH--, --NHCH₂ --, --CH₂ CO--, --COCH₂ --, --CH₂S(O)_(n) -- and --S(O)_(n) CH₂ -- (wherein n is 0,1 or 2);

Ar is phenyl which bears one or more substituents independently selectedfrom the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di- (1-6C)alkyl!amino,carbamoyl, (1-6C)alkylcarbamoyl, di- (1-6C)alkyl!carbamoyl,(1-6C)alkanoyl and oxime derivatives thereof and O-(1-6C)alkyl ethers ofsaid oximes, (1-6C)alkylthio, (1-6C)alkylsulphinyl and(1-6C)alkylsulphonyl when substituted by one or more groups selectedfrom (1-6C)alkoxycarbonyl, (1-6C)alkanoyl and oxime derivatives thereofand O-(1-6C)alkyl ethers of said oxime derivatives, (1-6C)alkanoylamino,(1-6C)alkanoyloxy, (1-6C)alkanoyloxy(1-6C)alkyl, carbamoyl,N-(1-6C)alkylcarbamoyl, N,N-di (1-6C)alkylcarbamoyl, amino,(1-6C)alkylamino, di- (1-6C)alkyl!amino, (1-6C)alkoxy, (2-6C)alkenyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,halogeno(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, phenyl, phenoxy,cyano, nitro, hydroxy and carboxy; and wherein Ar and/or a phenyl moietyin any of said groups mentioned above may optionally bear one or moresubstituents independently selected from halogeno, hydroxy, amino,nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di- (1-6C)alkyl!aminoN-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives; provided that when X is

--OCH₂ --, --NHCH₂ -- or --S(O)_(n) CH₂ -- (wherein n is 0,1 or 2), thenR¹ is not hydroxy; and provided that when a substituent on Ar includes aphenyl moiety, X is --OCH₂ --, then R¹ and R² are not both hydrogen, orjoined together so that CR¹ -CR² is a double bond.

In particular, according to the present invention there is provided acompound of formula I (formula set out hereinafter together with theother chemical formulae referred to herein), or a pharmaceuticallyacceptable salt thereof, wherein:

R¹ is hydrogen or hydroxy;

R² is hydrogen; or

R¹ and R² are joined together so that CR¹ -CR² is a double bond;

X is selected from --CH₂ CH₂ --, --CH═CH--, --C.tbd.C--, --CH₂ O--,--OCH₂ --, --CH₂ NH--, --NHCH₂ --, --CH₂ CO--, --COCH₂ --, --CH₂S(O)_(n) -- and --S(O)_(n) CH₂ -- (wherein n is 0,1 or 2);

Ar is phenyl which bears one or more substituents independently selectedfrom the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di- (1-6C)alkyl!amino,carbamoyl, (1-6C)alkylcarbamoyl, di- (1-6C)alkyl!carbamoyl,(1-6C)alkanoyl and oxime derivatives thereof and O-(1-6C)alkyl ethers ofsaid oximes, (1-6C)alkylthio, (1-6C)alkylsulphinyl and(1-6C)alkylsulphonyl when substituted by one or more groups selectedfrom (1-6C)alkoxycarbonyl, phenoxycarbonyl, (1-6C)alkanoyl, and oximederivatives thereof and O-(1-6C)alkyl ethers of said oxime derivatives,(1-6C)alkanoylamino, (1-6C)alkanoyloxy, (1-6C)alkanoyloxy(1-6C)alkyl,N-(1-6C)alkylcarbamoyl, N,N-di (1-6C)alkylcarbamoyl, amino,(1-6C)alkylamino, di- (1-6C)alkyl!amino, (1-6C)alkoxy, (2-6C)alkenyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,halogeno(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (2-6C)alkenyl,(2-6C)alkynyl, phenyl, phenoxy, cyano, nitro, hydroxy and carboxy; andwherein Ar and/or a phenyl moiety in any of said groups mentioned abovemay optionally bear one or more substituents independently selected fromhalogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-(1-6C)alkyl!amino N-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives; provided that when X is

--OCH₂ --, --NHCH₂ -- or --S(O)_(n) CH₂ -- (wherein n is 0,1 or 2), thenR¹ is not hydroxy; and provided that when a substituent on Ar includes aphenyl moiety, then R¹ is hydroxy.

It will be understood that when formula I compounds contain a chiralcentre, the compounds of the invention may exist in, and be isolated in,optically active or racemic form. The invention includes any opticallyactive or racemic form of a compound of formula I which possesses thebeneficial pharmacological effect of inhibiting squalene synthase. Thesynthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example by,resolution of a racemic form, by synthesis from optically activestarting materials or by asymmetric synthesis.

It will also be understood that, insofar as certain of the compounds ofthe formula I may exist as geometric isomers the present inventionincludes any such isomer which possesses the beneficial pharmacologicaleffect of inhibiting squalene synthase.

It is also to be understood that generic terms such as "alkyl" includeboth the straight chain and branched chain groups such as butyl andtert-butyl. However, when a specific term such as "butyl" is used, it isspecific for the straight chain or "normal" butyl group, branched chainisomers such as "t-butyl" being referred to specifically when intended.

It will be appreciated that when R and R² are joined so that CR¹ -CR² isa double bond, the heterocyclic ring in formula I will comprise the2,3-dehydroquinuclidine moiety shown in formula Ia.

A particular value for a group which may be present on Ar is, forexample,

    ______________________________________    for alkyl;   (1-4C)alkyl, such as methyl, ethyl, propyl,                 isopropyl, butyl, isobutyl or sec-butyl;    for alkenyl; (2-4C)alkenyl, such as allyl, prop-2-enyl,                 but-2-enyl or 2-methyl-2-propenyl;    for alkynyl; (2-4C)alkynyl, such as prop-2-ynyl or                 but-2-ynyl;    for alkoxy;  (1-4C)alkoxy, such as methoxy, ethoxy,                 propoxy, isopropoxy or butoxy;    for alkylamino;                 (1-4C)alkylamino, such as methylamino,                 ethylamino, propylamino or butylamino;    for di-alkylamino;                 di- (1-4C)alkylamino, such as dimethylamino,                 diethylamino, methylpropylamino or                 dipropylamino;    for alkylcarbamoyl;                 N-methylcarbamoyl, N-ethylcarbamoyl or                 N-propylcarbamoyl;    for di-alkylcarbamoyl;                 N,N-dimethylcarbamoyl or                 N,N-diethylcarbamoyl;    for alkoxycarbonyl;                 methoxycarbonyl, ethoxycarbonyl or                 propoxycarbonyl;    for alkoxycarbonyl-                 methoxycarbonylmethyl,    alkyl        methoxycarbonylethyl,                 ethoxycarbonylethyl or ethoxycarbonylmethyl;    for alkylthio;                 methylthio, ethylthio, propylthio, isopropylthio                 or butylthio;    for alkylsulphinyl;                 methylsulphinyl, ethylsulphinyl,                 propylsulphinyl, isopropylsulphinyl or                 butylsulphinyl;    for alkylsulphonyl;                 methylsulphonyl, ethylsulphonyl,                 propylsulphonyl, isoproylsulphonyl or                 butylsulphonyl;    for halogeno;                 fluoro, chloro, bromo or iodo;    for halogenoalkyl;                 halogenoalkyl containing one, two or three halo                 groups selected from fluoro, chloro, bromo and                 iodo and an alkyl group selected from methyl,                 ethyl, propyl, iso-propyl, butyl, iso-butyl and                 sec-butyl, (in particular fluoromethyl,                 difluoromethyl or trifluoromethyl);    for alkanoyl;                 formyl, acetyl, propionyl and butyryl;    for O-(1-6C)alkyl                 methyl, ethyl, propyl, isopropyl and butyl                 ethers    ethers of alkanoyl                 of said oximes;    oximes    for alkenyloxy;                 allyloxy and propenyloxy; and    for (1-4C)alkylenedioxy                 methylenedioxy, ethylenedioxy and                 trimethylenedioxy    for alkanoylamino;                 foramido, acetamido, propionamido,                 iso-propionamido, butyramido or                 iso-butyramido;    for alkoxyalkoxy;                 methoxyethoxy, ethoxymethoxy, ethoxyethoxy                 and methoxymethoxy;    for alkanoyloxy;                 acetyloxy and propionyloxy; and    for alkanoyloxyalkyl;                 acetyloxyziethyl, acetyloxyethyl,                 propionyloxymethyl and propionyloxy ethyl    ______________________________________

In particular Ar is phenyl which bears one or more substituentsindependently selected from (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-(1-6C)alkoxy(1-6C)alkyl!(1-6C)alkoxy, phenoxy(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxycarbonyl, di- (1-6C)alkoxy!(1-6C)alkyl,(1-6C)alkylamino(1-6C)alkyl, di- (1-6C)alkyl!amino(1-6C)alkyl,(1-6C)alkylcarbonylamino(1-6C)alkyl, (3-6C)cycloalkyl(1-6C)alkoxy,(2-6C)alkenyloxy(1-6C)alkyl, carbamoyl(1-6C)alkyl,N-(1-6C)alkylcarbamoyl(1-6C)alkyl, phenyl(1-6C)alkyl, N,N-di(1-6C)alkyl!carbamoyl(1-6C)alkyl; (1-6C)alkoxycarbonyl(2-6C)alkenyl,(1-6C)alkoxycarbonyl(2-6C)alkynyl, cyano(1-6C)alkoxy,cyano(1-6C)alkoxy(1-6C)alkyl, nitro(1-6C)alkoxy,nitro(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkylthio,(1-6C)alkoxycarbonyl(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkylthio(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl,(1-6C)alkoxycarbonyl(1-6C)alkylcarbamoyl,(1-6C)alkoxy(1-6C)alkylcarbamoyl, (1-6C)alkanoyloxy(1-6C)alkyl,cyano(1-6C)alkyl, carboxy(1-6C)alkyl, hydroxy(1-6C)alkyl(1-6C)alkylamino(1-6C)alkyl, di- (1-6C)alkyl!amino(1-6C)alkyl,(1-6C)alkylamino(1-6C)alkoxycarbonyl(1-6C)alkyl, di-(1-6C)alkyl!amino(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkylcarbamoyl(1-6C)alkoxycarbonyl, di-(1-6C)alkyl!carbamoyl(1-6C)alkoxycarbonyl,carbamoyl(1-6C)alkoxycarbonyl,(1-6C)alkoxycarbonyl(1-6C)alkoxy(1-6C)alkyl, di-(1-6C)alkyl!amino(1-6C)alkoxycarbonyl,(1-6C)alkoxycarbonyl(1-6C)alkanoyl,(1-6C)alkoxy(1-6C)alkoxy(1-6C)alkanoyl, (1-6C)alkylthio(1-6C)alkyl,(2-6C)alkenyl(1-6C)alkoxy(1-6C)alkyl,(2-6C)alkynyl(1-6C)alkoxy(1-6C)alkyl,halogeno(1-6C)alkyl(1-6C)alkoxycarbonyl, phenoxycarbonyl, di-(1-6C)alkoxycarbonyl!alkyl,(1-6c)alkoxycarbonyl(1-6C)alkanoyloxy(1-6C)alkyl,(1-6C)alkoxy(1-6c)alkanoyloxy(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl, hydroxy(1-6C)alkoxy,di-hydroxy(1-6C)alkyl, hydroxy(2-6C)alkenyl, hydoxy(2-6C)alkynyl,(1-6C)alkanoyl(1-6C)alkyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives; and, in addition,optionally bears one or more substituents independently selected fromhalogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-(1-6C)alkyl!amino N-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives.

More particularly, Ar is phenyl which bears one or more substituentsindependently selected from (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxycarbonyl(-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di- (1-6C)alkoxy!(1-6C)alkoxy,phenoxy(1-6C)alkoxy, (1-6C)alkoxycarbonyl(2-6C)alkenyl,(1-6C)alkoxycarbonyl(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxycarbonyl, (1-6C)alkylthio(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkylcarbamoyl,(1-6C)alkoxy(1-6C)alkylcarbamoyl, (1-6C)alkanoyloxy(1-6C)alkyl,cyano(1-6C)alkoxy, carboxy(1-6C)alkyl, cyano(1-6C)alkyl,phenyl(1-6C)alkyl, hydroxy(1-6C)alkyl,(1-6C)alkoxycarbonyl(1-6C)alkanoyl, (1-6C)alkylthio(1-6C)alkyl,(2-6C)alkenyl(1-6C)alkoxy(1-6C)alkyl, and (1-6C)alkanoyl(1-6C)alkyl andoxime derivatives thereof and O-(1-6C)alkyl ethers of said oximederivatives; and optionally bears one or more further substituentsselected from halogeno, hydroxy, amino, nitro, cyano, carboxy,carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di- (1-6C)alkyl!amino N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl,(1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oximederivatives thereof and O-(1-6C)alkyl ethers of said oxime derivatives.

In general, it is preferred that Ar is phenyl which bears one or moresubstituents selected from (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl,(1-6C)alkylthio(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxycarbonyl(1-6C)alkoxy, hydroxy(1-6C)alkyl,(1-6C)alkanoyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkanoyl andcarboxy(1-6C)alkyl; and optionally bears one or more furthersubstituents selected from halogeno, hydroxy, amino, nitro, cyano,carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-6C)alkylamino, di- (1-6C)alkyl!aminoN-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives.

More preferably, Ar is phenyl which bears a substituent selected from(1-6C)alkoxycarbonyl(1-6C)alkyl and carboxy(1-6C)alkyl, and whichoptionally bears one or more substituents selected from the optionalsubstituents defined in the preceding paragraph. (especially(2-6C)alkenyl such as allyl).

In general, for example, it is preferred that Ar bears one, two, threeor four substituents.

In particular, X is selected from --C.tbd.C--, --CH═CH, --CH₂ CH₂ --,--CH₂ O--, --CH₂ S(O)_(n) -- (n=0,1 or 2), --CH₂ NH--, --CH₂ CO-- and--COCH₂ ; more particularly from --C.tbd.C--, --CH═CH--, --CH₂ CH₂ --,--CH₂ O--, --CH₂ S-- and --CH₂ NH--.

In general it is preferred, for example, that R¹ is hydroxy and R² ishydrogen.

In general it is preferred, for example, that X is --C.tbd.C--, --CH₂CH₂ --, --CH₂ O or --CH--CH--, especially --C.tbd.C--.

In general, it is preferred, for example, that Ar is phenyl which bearsone or more (1-6C)alkoxycarbonyl(1-6C)alkyl substituents and which, inaddition, optionally bears one or more substituents selected from theoptional substituents defined above.

Specific values of interest for X include, for example, --C.tbd.C--,--CH═CH--, --CH₂ CH₂ -- and --CH₂ O--.

Specific values for R¹ and R² include, for example, R¹ is hydroxy and R²is hydrogen.

Specific values for Ar include, for example, phenyl which bears one ormore (particularly one or two) substituents selected from(1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl (such asmethoxyethoxycarbonylethyl), (1-6C)alkoxy(1-6C)alkyl (such asmethoxypropyl), (1-6C)alkoxycarbonyl(1-6C)alkyl (such asethoxycarbonylethyl, methoxycarbonylethyl, methoxycarbonylpropyl,methoxycarbonylbutyl, iso-butoxycarbonylethyl, hexyloxycarbonylethyl,methoxycarbonylpropyl, methoxycarbonylpentyl),(1-6C)alkoxycarbonyl(1-6C)alkoxy (such as methoxycarbonylmethoxy),(1-6C)alkoxy(1-6C)alkoxy (such as methoxyethoxy),(1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl (such as methoxyethoxymethyl,methoxyethoxyethyl), carboxy(1-6C)alkyl (such as carboxyethyl,carboxypropyl), hydroxyalkyl (such as hydroxymethyl),(1-6C)alkanoyl(1-6C)alkyl (such as ethanoylethyl) and oxime derivativesthereof and O-(1-6C)alkyl ethers of said oximes, and(1-6C)alkoxycarbonyl(1-6C)alkanoyl (such as ethoxycarbonylethanoyl,ethoxycarbonylpropanoyl); and optionally one or more substituentsselected from the optional substituents mentioned above and inparticular one or two substituents selected from (1-6C)alkyl (such asmethyl), (2-6C)alkenyl (such as allyl), halogeno (such as fluoro),(1-6C)alkoxy (such as methoxy) and (1-6C)alkanoyl (such as formyl).

Values of Ar of particular interest include those in which Ar is phenylwhich bears a substituent at the 4-position selected from(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylthio(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxycarbonyl(1-6C)alkoxy, hydroxy(1-6C)alkyl,(1-6C)alkanoyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkanoyl andcarboxy(1-6C)alkyl; and which optionally bears a substituent at the2-position selected from the optional substituents defined in thepreceding paragraph (especially (2-6C)alkenyl such as allyl).

In one embodiment of the present invention, R¹ and R² are both hydrogen;and X and Ar have any of the meanings defined above.

In a further embodiment of the present invention, R¹ and R² are joinedtogether so that CR¹ -CR² is a double bond; and X and Ar have any of themeanings defined above.

In a further embodiment of the present invention R¹ is hydroxy, R² ishydrogen; and X and Ar have any of the meanings defined above.

In a further embodiment there is provided a compound of formula I(formula set out hereinafter together with the other chemical formulaereferred to herein), or a pharmaceutically acceptable salt thereof,wherein:

R¹ is hydrogen or hydroxy;

R² is hydrogen; or

R¹ and R² are joined together so that CR¹ -CR² is a double bond;

X is selected from --CH₂ CH₂ --, --CH═CH--, --C.tbd.C--, --CH₂ O--,--OCH₂ --, --CH₂ NH--, --NHCH₂ --, --CH₂ CO--, --COCH₂ --, --CH₂S(O)_(n) -- and --S(O)_(n) CH₂ -- (wherein n is 0,1 or 2);

Ar is phenyl which bears one or more substituents independently selectedfrom the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di- (1-6C)alkyl!amino,carbamoyl, (1-6C)alkylcarbamoyl, di- (1-6C)alkyl!carbamoyl,(1-6C)alkanoyl and oxime derivatives thereof and O-(1-6C)alkyl ethers ofsaid oximes, (1-6C)alkylthio, (1-6C)alkylsulphinyl and(1-6C)alkylsulphonyl when substituted by one or more groups selectedfrom (1-6C)alkoxycarbonyl, (1-6C)alkanoyl and oxime derivatives thereofand O-(1-6C)alkyl ethers of said oxime derivatives, (1-6C)alkanoylamino,(1-6C)alkanoyloxy, (1-6C)alkanoyloxy(1-6C)alkyl, carbamoyl,N-(1-6C)alkylcarbamoyl, N,N-di (1-6C)alkylcarbamoyl, amino,(1-6C)alkylamino, di- (1-6C)alkyl!amino, (1-6C)alkoxy, (2-6C)alkenyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,halogeno(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, cyano, nitro, hydroxyand carboxy;

and wherein Ar and/or a phenyl moiety in any of said groups mentionedabove may optionally bear one or more substituents independentlyselected from halogeno, hydroxy, amino, nitro, cyano, carboxy,carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di- (1-6C)alkyl!amino N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl,(1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oximederivatives thereof and O-(1-6C)alkyl ethers of said oxime derivatives.provided that when X is

--OCH₂ --, --NHCH₂ -- or --S(O)_(n) CH₂ -- (wherein n is 0,1 or 2), thenR¹ is not hydroxy.

In a prefered embodiment of the present invention R¹ is hydroxy, R² ishydrogen, X is selected from --CH₂ CH₂ --, --CH═CH--, --C.tbd.C-- and--CH₂ O-- (especially --C.tbd.C--); Ar is phenyl which bears one or moresubstituents independently selected from(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-(1-6C)alkoxy!(1-6C)alkoxy, (1-6C)alkoxycarbonyl(2-6C)alkenyl,(1-6C)alkoxycarbonyl(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxycarbonyl, (1-6C)alkylthio(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkylcarbamoyl,(1-6C)alkoxy(1-6C)alkylcarbamoyl, (1-6C)alkanoyloxy(1-6C)alkyl,cyano(1-6C)alkoxy, carboxy(1-6C)alkyl, cyano(1-6C)alkyl,hydroxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkanoyl,(1-6C)alkylthio(1-6C)alkyl, (2-6C)alkenyl(1-6C)alkoxy(1-6C)alkyl, and(1-6C)alkanoyl(1-6C)alkyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives; and wherein Ar mayoptionally bear one or more substituents independently selected fromhalogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-(1-6C)alkyl!amino N-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives.

Particular, preferred and specific values include the appropriate valuesmentioned above.

In a specific embodiment, R¹ is hydroxy, R² is hydrogen X is selectedfrom --CH₂ CH₂ --, --CH═CH--, --C.tbd.C-- and --CH₂ O (especially--C.tbd.C--); Ar is phenyl which bears one or more substituents selectedfrom (1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, carboxy(1-6C)alkyl,(1-6C)alkanoyl(1-6C)alkyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oximes, (1-6C)alkoxycarbonyl(1-6C)alkanoyl;and wherein Ar and/or a phenyl moiety in any of said groups mentionedabove may optionally bear one or more substituents independentlyselected from halogeno, hydroxy, amino, nitro, cyano, carboxy,carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di- (1-6C)alkyl!amino N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl,(1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oximederivatives thereof and O-(1-6C)alkyl ethers of said oxime derivatives.

In an embodiment of particular interest R¹ is hydroxy, R² is hydrogen, Xis --C.tbd.C--, Ar is phenyl which bears a substituent selected from(1-6C)alkoxycarbonyl(1-6C)alkyl and carboxy(1-6C)alkyl, and whichoptionally bears a further substituent of (2-6C)alkenyl (such as allyl).

In a further embodiment of the present invention there is provided acompound of formula I (formula set out hereinafter together with theother chemical formulae referred to herein), or a pharmaceuticallyacceptable salt thereof, wherein:

R¹ is hydrogen or hydroxy;

R² is hydrogen; or

R¹ and R² are joined together so that CR¹ -CR² is a double bond;

X is selected from --CH₂ CH₂ --, --CH═CH--, --C.tbd.C--, --CH₂ O--,--OCH₂ --, --CH₂ NH--, --NHCH₂ --, --CH₂ CO--, --COCH₂ --, --CH₂S(O)_(n) -- and --S(O)_(n) CH₂ -- (wherein n is 0,1 or 2);

Ar is phenyl which bears one or more substituents independently selectedfrom the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di- (1-6C)alkyl!amino,(1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl whensubstituted by one or more groups selected from (1-6C)alkoxycarbonyl,phenoxycarbonyl, (1-6C)alkanoyl, (1-6C)alkanoylamino, (1-6C)alkanoyloxy,N-(1-6C)alkylcarbamoyl, N,N-di (1-6C)alkylcarbamoyl, (1-6C)alkoxy,(2-6C)alkenyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, phenyl, phenoxy, cyano,nitro, and hydroxy; and wherein Ar and/or a phenyl moiety in any of saidgroups mentioned above may optionally bear one or more substituentsindependently selected from halogeno, hydroxy, amino, nitro, cyano,carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-6C)alkylamino, di- (1-6C)alkyl!aminoN-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives; provided that when X is

--OCH₂ --, --NHCH₂ -- or --S(O)_(n) CH₂ -- (wherein n is 0,1 or 2), thenR¹ is not hydroxy; and provided that when a substituent on Ar includes aphenyl moiety, X is --OCH₂ --, then R¹ and R² are not both hydrogen, orjoined together so that CR¹ -CR² is a double bond.

In a further embodiment there is provided a compound of formula I(formula set out hereinafter together with the other chemical formulaereferred to herein), or a pharmaceutically acceptable salt thereof,wherein:

R¹ is hydrogen or hydroxy;

R² is hydrogen; or

R¹ and R² are joined together so that CR¹ -CR² is a double bond;

X is selected from --CH₂ CH₂ --, --CH═CH--, --C.tbd.C--, --CH₂ O--,--OCH₂ --, --CH₂ NH--, --NHCH₂ --, --CH₂ CO--, --COCH₂ --, --CH₂S(O)_(n) -- and --S(O)_(n) CH₂ -- (wherein n is 0,1 or 2);

Ar is phenyl which bears one or more substituents independently selectedfrom the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di- (1-6C)alkyl!amino,(1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl whensubstituted by one or more groups selected from (1-6C)alkoxycarbonyl,phenoxycarbonyl, (1-6C)alkanoyl, (1-6C)alkanoylamino, (1-6C)alkanoyloxy,N-(1-6C)alkylcarbamoyl, N,N-di (1-6C)alkylcarbamoyl, (1-6C)alkoxy,(2-6C)alkenyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, phenyl, phenoxy, cyano,nitro, and hydroxy; and wherein Ar and/or a phenyl moiety in any of saidgroups mentioned above may optionally bear one or more substituentsindependently selected from halogeno, hydroxy, amino, nitro, cyano,carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-6C)alkylamino, di- (1-6C)alkyl!aminoN-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives; provided that when X is

--OCH₂ --, --NHCH₂ -- or --S(O)_(n) CH₂ -- (wherein n is 0,1 or 2), thenR¹ is not hydroxy; and provided that when a substituent on Ar includes aphenyl moiety, then R¹ is hydroxy.

Particular, preferred and specific values include the appropriate valuesmentioned above.

In particular Ar is phenyl which bears one or more substituentsindependently selected from (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-(1-6C)alkoxy(1-6C)alkyl!(1-6C)alkoxy, phenoxy(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxycarbonyl, di- (1-6C)alkoxy!(1-6C)alkyl,(1-6C)alkylamino(1-6C)alkyl, di- (1-6C)alkyl!amino(1-6C)alkyl,(1-6C)alkylcarbonylamino(1-6C)alkyl, (3-6C)cycloalkyl(1-6C)alkoxy,(2-6C)alkenyloxy(1-6C)alkyl, carbamoyl(1-6C)alkyl,N-(1-6C)alkylcarbamoyl(1-6C)alkyl, phenyl(1-6C)alkyl, N,N-di-(1-6C)alkyl!carbamoyl(1-6C)alkyl; (1-6C)alkoxycarbonyl(2-6C)alkenyl,(1-6C)alkoxycarbonyl(2-6C)alkynyl, cyano(1-6C)alkoxy,cyano(1-6C)alkoxy(1-6C)alkyl, nitro(1-6C)alkoxy,nitro(1-6C)alkoxy(1-6C)alkyl, and (1-6C)alkoxycarbonyl(1-6C)alkylthio;and, in addition, optionally bears one or more substituentsindependently selected from halogeno, hydroxy, amino, nitro, cyano,carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-6C)alkylamino, di- (1-6C)alkyl!aminoN-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives.

More particularly, Ar is phenyl which bears one or more substituentsindependently selected from (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-1-6C)alkoxy(1-6C)alkyl!(1-6C)alkoxy, phenyloxy(1-6C)alkoxy,phenyl(1-4C)alkyl and (1-6C)alkoxy(1-6C)alkoxycarbonyl; and optionallybears one or more further substituents selected from halogeno, hydroxy,amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di- (1-6C)alkyl!aminoN-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives;

Specific values for Ar include, for example, phenyl which bears one ormore (particularly one or two) substituent selected from(1-6C)alkoxycarbonyl(1-6C)alkyl (such as ethoxycarbonylmethyl,methoxycarbonylmethyl, ethoxycarbonylethyl),(1-6C)alkoxycarbonyl(1-6C)alkoxy (such as ethoxycarbonylmethoxy),(1-6C)alkoxy(1-6C)alkoxy(such as methoxyethoxy or methoxyethoxy), di-1-6C)alkoxy(1-6C)alkyl!(1-6C)alkoxy (such as1-(methoxymethyl)-2-methoxyethoxy), (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl(such as methoxyethoxymethyl), phenoxy(1-6C)alkoxy (such asphenoxyethoxy), (1-6C)alkoxy(1-6C)alkoxycarbonyl (such asmethoxyethoxycarbonyl) and benzyl; and optionally one or more (inparticular, one or two) substituents selected from halogeno (such aschloro), (1-6C)alkanoylamino (such as propionamido), (1-6C)alkyl (suchas methyl) and (2-6C)alkenyl (such as allyl).

In a further embodiment of the present invention R¹ is hydroxy, R² ishydrogen, X is selected from --CH₂ CH₂ --, --CH═CH--, --C.tbd.C-- and--CH₂ O-- (especially --C.tbd.C--);

Ar is phenyl which bears one or more substituents independently selectedfrom (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-(1-6C)alkoxy(1-6C)alkyl!(1-6C)alkoxy, phenyloxy(1-6C)alkoxy,phenyl(1-4C)alkyl and (1-6C)alkoxy(1-6C)alkoxycarbonyl; and Aroptionally bears one or more further substituents selected fromhalogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-(1-6C)alkyl!amino N-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives.

Particular, preferred and specific values include the appropriate valuesmentioned above.

In a specific embodiment, R¹ is hydroxy, R² is hydrogen X is selectedfrom --CH₂ CH₂ --, --CH--CH--, --C.tbd.C-- and --CH₂ O (especially--C.tbd.C--);

Ar is phenyl which bears a substituent selected from(1-6C)alkoxycarbonyl(1-6C)alkyl (such as ethoxycarbonylmethyl,methoxycarbonylmethyl, ethoxycarbonylethyl),(1-6C)alkoxycarbonyl(1-6C)alkoxy (such as ethoxycarbonylmethoxy),(1-6C)alkoxy(1-6C)alkoxy(such as methoxyethoxy or methoxyethoxy), di-1-6C)alkoxy(1-6C)alkyl!(1-6C)alkoxy (such as1-(methoxymethyl)-2-methoxyethoxy), (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl(such as methoxyethoxymethyl), phenoxy(1-6C)alkoxy (such asphenoxyethoxy), (1-6C)alkoxy(1-6C)alkoxycarbonyl (such asmethoxyethoxycarbonyl) and benzyl; and optionally one or more (inparticular, one or two) substituents selected from halogeno (such aschloro), (1-6C)alkanoylamino (such as propionamido), (1-6C)alkyl (suchas methyl) and (2-6C)alkenyl (such as allyl).

In a further embodiment there is provided a compound of formula I(formula set out hereinafter together with the other chemical formulaereferred to herein), or a pharmaceutically acceptable salt thereof,wherein:

R¹ is hydrogen or hydroxy;

R² is hydrogen; or

R¹ and R² are joined together so that CR¹ -CR² is a double bond;

X is selected from --CH₂ CH₂ --, --CH═CH--, --C.tbd.C--, --CH₂ O--,--OCH₂ --, --CH₂ NH--, --NHCH₂ --, CH₂ CO--, --COCH₂ --, --CH₂ S(O)_(n)-- and --S(O)_(n) CH₂ -- (wherein n is 0,1 or 2);

Ar is phenyl which bears one or more substituents independently selectedfrom the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di- (1-6C)alkyl!amino,carbamoyl, (1-6C)alkylcarbamoyl, di- (1-6C)alkyl!carbamoyl,(1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl whensubstituted by one or more groups selected from (1-6C)alkoxycarbonyl,phenoxycarbonyl, (1-6C)alkanoyl, (1-6C)alkanoylamino, (1-6C)alkanoyloxy,N-(1-6C)alkylcarbamoyl, N,N-di (1-6C)alkylcarbamoyl, (1-6C)alkoxy,(2-6C)alkenyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, phenyl, phenoxy, cyano,nitro, hydroxy and carboxy;

and wherein Ar and/or a phenyl moiety in any of said groups mentionedabove may optionally bear one or more substituents independentlyselected from halogeno, hydroxy, amino, nitro, cyano, carboxy,carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di- (1-6C)alkyl!amino N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl,(1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oximederivatives thereof and O-(1-6C)alkyl ethers of said oxime derivatives.provided that when X is

--OCH₂ --, --NHCH₂ -- or --S(O)_(n) CH₂ -- (wherein n is 0,1 or 2), thenR¹ is not hydroxy; and provided that when a substituent on Ar includes aphenyl moiety, X is --OCH₂ --, then R¹ and R² are not both hydrogen, orjoined together so that CR¹ -CR² is a double bond.

In particular, according to the present invention there is provided acompound of formula I (formula set out hereinafter together with theother chemical formulae referred to herein), or a pharmaceuticallyacceptable salt thereof, wherein:

R¹ is hydrogen or hydroxy;

R² is hydrogen; or

R¹ and R² are joined together so that CR¹ -CR² is a double bond;

X is selected from --CH₂ CH₂ --, --CH═CH--, --C.tbd.C--, --CH₂ O--,--OCH₂ --, --CH₂ NH--, --NHCH₂ --, --CH₂ CO--, --COCH₂ --, --CH₂S(O)_(n) -- and --S(O)_(n) CH₂ -- (wherein n is 0,1 or 2);

Ar is phenyl which bears one or more substituents independently selectedfrom the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di- (1-6C)alkyl!amino,carbamoyl, (1-6C)alkylcarbamoyl, di- (1-6C)alkyl!carbamoyl,(1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl whensubstituted by one or more groups selected from (1-6C)alkoxycarbonyl,phenoxycarbonyl, (1-6C)alkanoyl, (1-6C)alkanoylamino, (1-6C)alkanoyloxy,N-(1-6C)alkylcarbamoyl, N,N-di (1-6C)alkylcarbamoyl, (1-6C)alkoxy,(2-6C)alkenyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, phenyl, phenoxy, cyano,nitro, hydroxy and carboxy;

and wherein Ar and/or a phenyl moiety in any of said groups mentionedabove may optionally bear one or more substituents independentlyselected from halogeno, hydroxy, amino, nitro, cyano, carboxy,carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di- (1-6C)alkyl!amino N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl,(1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oximederivatives thereof and O-(1-6C)alkyl ethers of said oxime derivatives;provided that when X is

--OCH₂ --, NRCH₂ -- or --S(O)_(n) CH₂ -- (wherein n is 0,1 or 2), thenR¹ is not hydroxy; and provided that when a substituent on Ar includes aphenyl moiety, then R¹ is hydroxy.

Particular, preferred and specific values include the appropriate valuesmentioned above.

In particular Ar is phenyl which bears one or more substituentsindependently selected from (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-(1-6C)alkoxy(1-6C)alkyl!(1-6C)alkoxy, phenoxy(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxycarbonyl, di- (1-6C)alkoxy!(1-6C)alkyl,(1-6C)alkylamino(1-6C)alkyl, di- (1-6C)alkyl!amino(1-6C)alkyl,(1-6C)alkylcarbonylamino(1-6C)alkyl, (3-6C)cycloalkyl(1-6C)alkoxy,(2-6C)alkenyloxy(1-6C)alkyl, carbamoyl(1-6C)alkyl,N-(1-6C)alkylcarbamoyl(1-6C)alkyl, phenyl(1-6C)alkyl, N,N-di-(1-6C)alkyl!carbamoyl(1-6C)alkyl; (1-6C)alkoxycarbonyl(2-6C)alkenyl,(1-6C)alkoxycarbonyl(2-6C)alkynyl, cyano(1-6C)alkoxy,cyano(1-6C)alkoxy(1-6C)alkyl, nitro(1-6C)alkoxy,nitro(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkylthio,(1-6C)alkoxycarbonyl(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkylthio(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl,(1-6C)alkoxycarbonyl (1-6C)alkylcarbamoyl,(1-6C)alkoxy(1-6C)alkylcarbamoyl, (1-6C)alkanoyloxy(1-6C)alkyl,cyano(1-6C)alkyl, carboxy(1-6C)alkyl and hydroxy(1-6C)alkyl; and, inaddition, optionally bears one or more substituents independentlyselected from halogeno, hydroxy, amino, nitro, cyano, carboxy,carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di- (1-6C)alkyl!amino N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl,(1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oximederivatives thereof and O-(1-6C)alkyl ethers of said oxime derivatives.

More particularly, Ar is phenyl which bears one or more substituentsindependently selected from (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di- (1-6C)alkoxy!(1-6C)alkoxy,phenoxy(1-6C)alkoxy, (1-6C)alkoxycarbonyl(2-6C)alkenyl,(1-6C)alkoxycarbonyl(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxycarbonyl, (1-6C)alkylthio(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkylcarbamoyl,(1-6C)alkoxy(1-6C)alkylcarbamoyl, (1-6C)alkanoyloxy(1-6C)alkyl,cyano(1-6C)alkoxy, carboxy(1-6C)alkyl, cyano(1-6C)alkyl,phenyl(1-6C)alkyl, hydroxy(1-6C)alkyl; and optionally bears one or morefurther substituents selected from halogeno, hydroxy, amino, nitro,cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-6C)alkylamino, di- (1-6C)alkyl!aminoN-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives.

In general, it is preferred that Ar is phenyl which bears one or moresubstituents selected from (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl,(1-6C)alkylthio(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl andcarboxy(1-6C)alkyl; and optionally bears one or more furthersubstituents selected from halogeno, hydroxy, amino, nitro, cyano,carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-6C)alkylamino, di- (1-6C)alkyl!aminoN-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives.

In a further embodiment there is provided there is provided a compoundof formula I (formula set out hereinafter together with the otherchemical formulae referred to herein), or a pharmaceutically acceptablesalt thereof, wherein:

R is hydrogen or hydroxy;

R² is hydrogen; or

R¹ and R² are joined together so that CR¹ -CR² is a double bond;

X is selected from --CH₂ CH₂ --, --CH═CH--, --C.tbd.C--, --CH₂ O--,--OCH₂ --, --CH₂ NH---, --NHCH₂ --, --CH₂ CO--, --COCH₂ --, --CH₂S(O)_(n) -- and --S(O)_(n) CH₂ -- (wherein n is 0,1 or 2);

Ar is phenyl which bears one or more substituents independently selectedfrom the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di- (1-6C)alkyl!amino,carbamoyl, (1-6C)alkylcarbamoyl, di- (1-6C)alkyl carbamoyl,(1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl whensubstituted by one or more groups selected from (1-6C)alkoxycarbonyl,(1-6C)alkanoyl and oxime derivatives thereof and O-(1-6C)alkyl ethers ofsaid oxime derivatives, (1-6C)alkanoylamino, (1-6C)alkanoyloxy,N-(1-6C)alkylcarbamoyl, N,N-di (1-6C)alkylcarbamoyl, amino,(1-6C)alkylamino, di- (1-6C)alkylamino, (1-6C)alkoxy, (2-6C)alkenyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,halogeno(1-6C)alkyl, phenyl, phenoxy, cyano, nitro, hydroxy and carboxy;

and wherein Ar and/or a phenyl moiety in any of said groups mentionedabove may optionally bear one or more substituents independentlyselected from halogeno, hydroxy, amino, nitro, cyano, carboxy,carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di- (1-6C)alkyl!amino N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl,(1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oximederivatives thereof and O-(1-6C)alkyl ethers of said oxime derivatives.provided that when X is

--OCH₂ --, --NHCH₂ -- or --S(O)_(n) CH₂ -- (wherein n is 0,1 or 2), thenR¹ is not hydroxy; and provided that when a substituent on Ar includes aphenyl moiety, X is --OCH₂ --, then R¹ and R² are not both hydrogen, orjoined together so that CR¹ -CR² is a double bond.

In particular, according to the present invention there is provided acompound of formula I (formula set out hereinafter together with theother chemical formulae referred to herein), or a pharmaceuticallyacceptable salt thereof, wherein:

R¹ is hydrogen or hydroxy;

R² is hydrogen; or

R¹ and R² are joined together so that CR¹ -CR² is a double bond;

X is selected from --CH₂ CH₂ --, --CH═CH--, --C.tbd.C--, --CH₂ O--,--OCH₂ --, --CH₂ NH--, --NHCH₂ --, --CH₂ CO--, --COCH₂ --, --CH₂S(O)_(n) -- and --S(O)_(n) CH₂ -- (wherein n is 0,1 or 2);

Ar is phenyl which bears one or more substituents independently selectedfrom the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di- (1-6C)alkyl!amino,carbamoyl, (1-6C)alkylcarbamoyl, di- (1-6C)alkyl!carbamoyl,(1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl whensubstituted by one or more groups selected from (1-6C)alkoxycarbonyl,phenoxycarbonyl, (1-6C)alkanoyl, and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives, (1-6C)alkanoylamino,(1-6C)alkanoyloxy, N-(1-6C)alkylcarbamoyl, N,N-di (1-6C)alkylcarbamoyl,amino, (1-6C)alkylamino, di- (1-6C)alkyl!amino, (1-6C)alkoxy,(2-6C)alkenyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, phenyl, phenoxy, cyano,nitro, hydroxy and carboxy;

and wherein Ar and/or a phenyl moiety in any of said groups mentionedabove may optionally bear one or more substituents independentlyselected from halogeno, hydroxy, amino, nitro, cyano, carboxy,carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di- (1-6C)alkyl!amino N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl,(1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oximederivatives thereof and O-(1-6C)alkyl ethers of said oxime derivatives;provided that when X is

--OCH₂ --, --NHCH₂ -- or --S(O)_(n) -- CH₂ -- (wherein n is 0,1 or 2),then R¹ is not hydroxy; and provided that when a substituent on Arincludes a phenyl moiety, then R¹ is hydroxy.

In particular Ar is phenyl which bears one or more substituentsindependently selected from (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-(1-6C)alkoxy(1-6C)alkyl!(1-6C)alkoxy, phenoxy(1-6C)alkoxy,h(1-6C)alkoxy(1-6C)alkoxycarbonyl, di- (1-6C)alkoxy!(1-6C)alkyl,(1-6C)alkylamino(1-6C)alkyl, di- (1-6C)alkyl!amino(1-6C)alkyl,(1-6C)alkylcarbonylamino(1-6C)alkyl, (3-6C)cycloalkyl(1-6C)alkoxy,(2-6C)alkenyloxy(1-6C)alkyl, carbamoyl(1-6C)alkyl,N-(1-6C)alkylcarbamoyl(1-6C)alkyl, phenyl(1-6C)alkyl, N,N-di-(1-6C)alkyl!carbamoyl(1-6C)alkyl; (1-6C)alkoxycarbonyl(2-6C)alkenyl,(1-6C)alkoxycarbonyl(2-6C)alkynyl, cyano(1-6C)alkoxy,cyano(1-6C)alkoxy(1-6C)alkyl, nitro(1-6C)alkoxy,nitro(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkylthio,(1-6C)alkoxycarbonyl(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkylthio(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl,(1-6C)alkoxycarbonyl(1-6C)alkylcarbamoyl,(1-6C)alkoxy(1-6C)alkylcarbamoyl, (1-6C)alkanoyloxy(1-6C)alkyl,cyano(1-6C)alkyl, carboxy(1-6C)alkyl, hydroxy(1-6C)alkyl(1-6C)alkylamino(1-6C)alkyl, di- (1-6C)alkyl!amino(1-6C)alkyl,(1-6C)alkylamino(1-6C)alkoxycarbonyl(1-6C)alkyl, di-(1-6C)alkyl!amino(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkylcarbamoyl(1-6C)alkoxycarbonyl, di-(1-6C)alkyl!carbamoyl(1-6C)alkoxycarbonyl,carbamoyl(1-6C)alkoxycarbonyl,(1-6C)alkoxycarbonyl(1-6C)alkoxy(1-6C)alkyl, di-(1-6C)alkyl!amino(1-6C)alkoxycarbonyl,(1-6C)alkoxycarbonyl(1-6C)alkanoyl,(1-6C)alkoxy(1-6C)alkoxy(1-6C)alkanoyl, (1-6C)alkylthio(1-6C)alkyl,(2-6C)alkenyl(1-6C)alkoxy(1-6C)alkyl,(2-6C)alkynyl(1-6C)alkoxy(1-6C)alkyl,halogeno(1-6C)alkyl(1-6C)alkoxycarbonyl, phenoxycarbonyl,(1-6C)alkanoyl(1-6C)alkyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives; and, in addition,optionally bears one or more substituents independently selected fromhalogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-(1-6C)alkylamino N-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives.

More particularly, Ar is phenyl which bears one or more substituentsindependently selected from (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di- (1-6C)alkoxy!(1-6C)alkoxy,phenoxy(1-6C)alkoxy, (1-6C)alkoxycarbonyl(2-6C)alkenyl,(1-6C)alkoxycarbonyl(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxycarbonyl, (1-6C)alkylthio(1-6C)alkoxy,(1-6c)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkylcarbamoyl,(1-6C)alkoxy(1-6C)alkylcarbamoyl, (1-6C)alkanoyloxy(1-6C)alkyl,cyano(1-6C)alkoxy, carboxy(1-6C)alkyl, cyano(1-6C)alkyl,phenyl(1-6C)alkyl, hydroxy(1-6C)alkyl,(1-6C)alkoxycarbonyl(1-6C)alkanoyl, (1-6C)alkylthio(1-6C)alkyl,(2-6C)alkenyl(1-6C)alkoxy(1-6C)alkyl, and (1-6C)alkanoyl(1-6C)alkyl andoxime derivatives thereof and O-(1-6C)alkyl ethers of said oximederivatives; and optionally bears one or more further substituentsselected from halogeno, hydroxy, amino, nitro, cyano, carboxy,carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di- (1-6C)alkyl!amino N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl,(1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oximederivatives thereof and O-(1-6C)alkyl ethers of said oxime derivatives.

In general, it is preferred that Ar is phenyl which bears one or moresubstituents selected from (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl,(1-6C)alkylthio(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl(1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxycarbonyl(1-6C)alkoxy, hydroxy(1-6C)alkyl,(1-6C)alkanoyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkanoyl, andcarboxy(1-6C)alkyl; and optionally bears one or more furthersubstituents selected from halogeno, hydroxy, amino, nitro, cyano,carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-6C)alkylamino, di- (1-6C)alkyl!aminoN-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives.

Compounds of the invention which are of particular interest include thecompounds described in the accompanying Examples (and theirpharmaceutically-acceptable salts), and are hence provided as a furtherfeature of the present invention. In particular, the present inventionprovides a compound as described in Example 1, 23, 26, 27, 28, 30, 35,44, 55, 65, 66, 67, 68, 69, 83, 84, 85, 115 and 120 and theirpharmaceutically acceptable salts.

A suitable pharmaceutically-acceptable salt of the present inventioncomprises an acid-addition salt derived from an inorganic or organicacid which provides a pharmaceutically-acceptable anion. Thus, examplesof salts of the present invention include acid-addition salts withhydrochloric, hydrobromic, nitric, sulphuric, phosphoric,trifluoroacetic, citric, tartaric, succinic, maleic, fumaric or aceticacid. In addition, suitable pharmaceutically-acceptable salts includewhere the compound of formula I is sufficiently acidic, for examplewhere the compound of formula I bears an acidic substituent such ascarboxy! those formed with a base which affords a pharmaceuticallyacceptable cation. Suitable bases include an alkali metal salt (such asa sodium or potassium salt), an alkaline earth metal salt (such as acalcium or magnesium salt), an ammonium salt or a salt with an organicbase which affords a physiologically-acceptable cation such as a saltwith methylamine, dimethylamine, triethylamine, piperidine ormorpholine.

The compounds of the present invention may be obtained by standardprocedures of organic chemistry already known to be applicable to thepreparation of structurally analogous compounds. Such procedures for thepreparation of the compounds of formula I, or pharmaceuticallyacceptable salts thereof, are provided as a further feature of thepresent invention and are illustrated by the following preferredprocesses in which the various generic radicals, for example, R¹, R², Xand Ar may take any of the meanings hereinbefore defined.

Thus, according to the present invention there is also provided aprocess for preparing a compound of formula I, or apharmaceutically-acceptable salt thereof, which process comprises:

(a) For those compounds of formula I in which R¹ and R² are bothhydrogen, reducing a compound of formula I in which R¹ and R² are joinedtogether so that CR¹ -CR² is a double bond.

The reduction may be carried out, for example, by catalytichydrogenation, or by reaction with a suitable reducing agent. Suitablereaction conditions include, for example, catalytic hydrogenation usinga catalyst which comprises a noble metal. Particular catalysts includepalladium, platinum and nickel (especially when in the finely dividedstate known as raney nickel), and catalysts in which the noble metal issupported on an inert carrier such as carbon. A specific example of asupported catalyst is Pd/C. The reduction is conveniently carried out ina solvent of, for example, an alcohol (such as ethanol), and at (ornear) ambient temperature and optionally under pressure.

Further suitable reaction conditions include, for example, reductionwith a borane such as diborane. The reaction is generally carried out inan inert solvent of, for example, tetrahydrofuran or methyl t-butylether at, for example, 0-60° C. It may be preferable to cool thereaction below ambient temperature (eg. to about 0° C.) during thereduction. The borane generated may be hydrolysed by treatment with anorganic acid such as acetic acid, which hydrolysis may be carried out at0-60° C., and may be accelerated by heating (eg. refluxing).

(b) For compounds of formula I in which R¹ and R² are joined together sothat CR ¹ -CR² is a double bond, dehydrating a compound of formula I inwhich R¹ is hydroxy and R² is hydrogen.

The dehydration may be carried out using an acid such as sulphuric acid(eg. concentrated sulphuric acid), or p-toluene sulphonic acid. Thereaction is conveniently carried out with heating, and conveniently aninert solvent is employed. For example, the reaction may be carried outusing sulphuric acid at temperatures of about 70-130° C.; or usingp-toluene sulphonic acid in a hydrocarbon solvent of, for example,toluene or xylene at ambient temperature to reflux, and preferably atreflux. The dehydration may also be carried out using trifluoroaceticacid in an inert solvent such as dichloromethane (at ambient temperatureto reflux temperature).

(c) For compounds of formula I in which R¹ and R² are joined together sothat CR ¹ -CR² is a double bond, treating a compound of formula II inwhich Z is a leaving group with a base.

Suitable values for Z include, for example, halogen such as chloro,bromo, iodo, or a methylsulphonyloxy or toluenesulphonyloxy group.Suitable bases include hydroxide (such as potassium or sodiumhydroxide), and alkoxide (such as potassium t-butoxide or sodiumethoxide).

The reaction is conveniently carried out in the presence of a solvent,preferably a polar organic solvent. Suitable solvents include, forexample, an alcohol (such as ethanol), or an aprotic solvent such asdimethylformamide or N-methylpyrrolidone. The reaction may be carriedout at ambient temperature or at an elevated temperature, such as at atemperature between ambient and the reflux temperature of the reactionmixture. This method is generally preferred over that described in (b)when X is --OCH₂ -- or --SCH₂ --.

The compounds of formula II may be prepared from a compound of formula Iin which R¹ is hydroxy. For example, where Z is halogen the compound offormula I in which R¹ is hydroxy and R² is hydrogen may be reacted withthe appropriate phosphorous halide (eg. PCl₅, PBr₃ or PI₃), or where Zis chloro, by reaction with thionyl chloride. The compound of formula Iin which R¹ is hydroxy may be reacted with mesyl chloride to thecompound in which Z is methylsulphonyloxy; and with tosyl chloride togive Z is toluene sulphonyloxy.

(d) For those compounds of formula I in which X is --CH₂ CO--, reactingan organometallic compound of formula III in which M is a metal atom ora derivative thereof, with a compound of formula IV.

Suitable values for M include, for example, magnesium and lithium. Inthe case where M is magnesium it is conveniently present in the form ofa derivative of formula --MgX where X is a halogen atom such as iodo orbromo, so that the organometallic compound of formula III is in the formknown as a Grignard Reagent. The reaction is generally carried out in aninert solvent such as dry diethyl ether or tetrahydrofuran. For example,the reaction may be carried out at a temperature between 0° C. and thereflux temperature of the reaction mixture.

The compounds of formula III may be prepared from the correspondingcompound of formula Ar-"hal" in which "hal" is a halogen atom, such asiodo or bromo as is well known in the art.

e) For those compounds of formula I in which X is --CH₂ --NH-- or--NHCH₂ --, reducing a compound of formula I in which X is --CH═N-- or--N═CH-- (as appropriate).

The reaction may be carried out using a chemical reducing agent such asa hydride in a solvent such as an alcohol at ambient temperature. Thus,in a particular example, the reduction may be carried out using sodiumborohydride in a solvent such as methanol at ambient temperature. Thereduction may also be carried out by selective catalytic hydrogenationusing similar conditions to those described under (a) above.

It will be appreciated that the preferred method of reduction willdepend upon the value of X. Thus, for example, where debenzylation ispossible (eg. when X is --NHCH₂ --), it is generally preferred that achemical reducing agent is employed.

The compounds of formula I in which X is --CH═N-- may be prepared byreaction of a compound of formula V with a compound of formula VI. Thereaction is generally carried out in an inert hydrocarbon solvent suchas toluene or benzene, with heating (eg. at reflux) and the reaction maybe accelerated by removing water generated in the reaction by azeotropicdistillation. Similarly, the compounds of formula I in which X is--N═CH-- may be prepared by reaction of a compound of formula VII with acompound of formula VIII.

f) For those compounds of formula I in which X is --CH₂ NH--, --CH₂ O--,--CH₂ S--, R¹ is hydroxy and R² is hydrogen, reacting a compound offormula IX in which Z is --NH₂, --OH or SH as appropriate with acompound of formula X.

The reaction is conveniently carried out in a solvent such an inerthydrocarbon eg. toluene with heating. The reaction may be facilitated bythe presence of acid or base.

The compound of formula X is conveniently generated in situ, by, forexample, treating quinuclidin-3-one with trimethylsulphoxonium iodide inthe presence of a base of, for example, an alkali metal hydride such assodium hydride and in a solvent such as dimethylformamide, or an alkalimetal hydroxide such as sodium hydroxide in a solvent such as an aqueoussolvent.

The compound of formula X may also be prepared from a "halohydrin" as iswell known in the art. The halohydrin may be prepared, for example, byaddition of HOCl to the corresponding olefin and the halohydrin treatedwith base (eg. NaOH) to give the compound of formula X.

g) For compounds of formula I in which X is --CH═CH--, reacting acompound of formula XI with a compound of formula V in the presence of abase.

Suitable bases include alkoxides, such as potassium t-butoxide, and thereaction is conveniently carried out in an inert solvent such astetrahydrofuran with cooling below ambient temperature eg -40° C. to 0°C.); and metal hydrides such as sodium hydride in a solvent such asdimethyl formamide or dimethyl suphoxide. A particularly suitable baseis, for example, sodium dimsyl which may conveniently be used in asolvent such as dimethyl sulphoxide.

The compounds of formula XI may be prepared by reaction of a compound offormula ArCH₂ -hal in which "hal" is halogen, such as chloro, withtriphenylphosphine as is well known in the art.

h) For those compounds of formula I in which X is --CH₂ CH₂ --, reducinga compound of formula I in which X is --CH═CH-- or in which X is--C.tbd.C--.

The reaction may conveniently be carried out by catalytic hydrogenationusing conditions similar to those mentioned in (a) above.

In an alternative synthesis a compound of formula ArCH₂ CH₂ -hal wherein"hal" represents a halogen atom such as bromo, is reacted withquinuclidin-3-one in the presence of sec-butyl lithium, with cooling (eg-70° C.) in an inert solvent such as tetrahydrofuran.

i) For compounds of formula I in which X is --COCH₂ --, reacting acompound of formula XII in which M is a metal atom or a derivativethereof, with a compound of formula XIII.

Suitable values for M and suitable reaction conditions are thosementioned in (d) above. The compounds of formula III may be preparedfrom the corresponding halogeno compound in a manner analogous to thepreparation of compounds of formula III discussed in (d) above.

j) For those compounds of formula I in which X is --CH₂ O-- or --CH₂S--, reacting a compound of formula XIV with a compound of formula XV,in which Z¹ is a leaving group and Z² is --YM, or Z¹ is --YM and Z² is aleaving group, and wherein Y is oxygen or sulphur (as appropriate) and his a metal atom.

Suitable leaving groups include, for example, halogen (such as chloro,bromo or iodo), methanesulphonyloxy, toluenesulphonyloxy ortrifluoromethanesulphonyloxy; and suitable metals include, for examplesodium and lithium.

The process is generally performed in the presence of a suitablesolvent, for example, a hydrocarbon, such as toluene or xylene, or anether such as dioxan or tetrahydrofuran, and at a temperature in therange, for example 20-150° C.

It may be desirable to protect the quinuclidine nitrogen atom during thereaction, especially when Z¹ is --YM, as described in (1) below. It maybe desirable to protect R¹ when it represents a hydroxy group as, forexample, a silyl ether.

k) For those compounds of formula I in which X is --OCH₂ -- or --SCH₂ --and R¹ and R² are both hydrogen, reacting a compound of formula XVI inwhich Y is oxygen or sulphur as appropriate with a compound of formulaXVII in which Z is a leaving group.

Suitable leaving groups include halogen, such as chloro, bromo or iodo,methanesulphonyloxy and toluenesulphonyloxy. The reaction is generallycarried out in the presence of a base such as an alkali metal hydroxide,eg sodium or potassium hydroxide, and in a solvent such as dimethylsulphoxide or dimethylformamide.

1) For compounds of formula I in which X is --OCH₂ --, --SCH₂ --,--CH2O--, or --CH₂ S--, deprotecting a compound of formula XVIII inwhich Q is a protecting group.

Suitable values for Q include, for example, --BH₃ -- or an oxygen atom.When Q is --BH₃ the deprotection may be carried out by treatment with anacid such as hydrochloric acid in acetone. When Q is an oxygen atomdeprotection may be carried out by reduction using a suitable reducingagent such as sulphur dioxide.

The compounds of formula XVIII in which X is --CH₂ O-- or --CH₂ S-- maybe prepared by methods analogous to those described in (j), and in whichX is --OCH₂ -- or --SCH₂ -- by methods analogous to those described in(k) above, but in which the starting material containing thequinuclidine moiety is protected by Q. A preferred way of preparingcompounds of formula XVIII in which X is --CH₂ O-- or --CH₂ S-- and R¹is hydroxy and R is hydrogen is by a procedure analogous to thatdescribed in (f) in which the compound of formula X is protected by Q.The quinuclidine moiety in the various starting materials may beprotected using methodology well known in the art. Thus, for example,those in which Q is BR₃ may be prepared by reaction of the appropriatequinuclidine moiety with BH₃.THF, generally with cooling (for example at-70° C.); whilst those in which Q is an oxygen atom may be prepared byoxidation of the appropriate quinuclidine moiety with, for example, 30%hydrogen peroxide.

m) For those compounds of formula I in which X is --C.tbd.C--, reactinga compound of formula I in which X is --CH═CH-- with a halogen, followedby treatment with a base.

A suitable halogen is bromine and the reaction is conveniently carriedout in an inert solvent such as carbon tetrachloride. Suitable basesinclude, for example, potasium t-butoxide. This treatment isconveniently carried out in a solvent such as THF, with. heating (eg. ata temperature between ambient and about 70° C.).

n) For those compounds of formula I in which R¹ is hydroxy, R² ishydrogen and X is --C.tbd.C--, reacting a compound of formula XIX inwhich H is a metal atom, with quinuclidin-3-one.

A suitable metal is lithium and suitable reaction conditions includethose mentioned in (d) above.

o) For those compounds in which R¹ and R² are hydrogen and X is--C.tbd.C--, reacting a compound of formula XIX in which M is a metalatom with a compound of formula XV in which Z is a leaving group.

Suitable values for Z include, for example, halogen (such as chloro,bromo or iodo), methanesulphonyloxy, toluenesulphonyloxy ortrifluoromethanesulphonyloxy; suitable values for M include, forexample, lithium; and suitable reaction conditions include thosementioned under (d) above.

p) For those compounds in which X is --C.tbd.C-- and R¹ is hydrogen orhydroxy and R² is hydrogen, reacting a compound of formula XX with acompound of formula IX in which Z is a leaving group in the presence ofa catalyst.

Suitable catalysts include, for example, transition metal complexes suchas palladium or nickel complexes. Particular catalysts are palladium(II) complexes, a specific example of which is Pd(PPh₃)₂ Cl₂. Suitablevalues for Z include, for example, halogen (such as chloro, bromo oriodo), methanesulphonyloxy, toluenesulphonyloxy andtrifluoromethanesulphonyloxy. The reaction is generally carried out inthe presence of a base, for example, an amine such as triethylamine andin a solvent such as dimethylformamide with heating (for example at 60to 100° C.). The reaction is preferably carried out in the prersence ofcopper(I)iodide. Compounds of formula XX may be prepared according toScheme 1a and 2b.

q) For those compounds in which X is --C═C-- and R¹ is hydrogen orhydroxy and R² is hydrogen, reacting a compound of formula XXI with acompound of formula IX in which Z is a leaving group in the presence ofa catalyst.

Suitable reaction conditions are those mentioned under (p) above.Compounds of formula XXI may be prepared according to Scheme 1b and 2a.

r) For those compounds in which X is --CH═CH--, reducing a compound offormula I in which X is --C.tbd.C--.

The reaction may be carried out by catalytic hydrogenation usingconditions similar to those mentioned in (a) above. A particularlysuitable catalyst is, for example, Lindlars catalyst (Pd on BaSO₄poisoned with quinoline). The reaction may also be carried out using areducing agent such as trhose mentioned under (a) above or lithiumaluminium hydride in a suitable solvent such as diethylether at ambienttemperature or with cooling.

s) For those compounds of formula I in which X is --CH═CH--, reacting acompound of formula XXII in which L is a suitable ligand with a compoundof formula IX in which Z is a leaving group in the presence of acatalyst.

Suitable values for L include, for example, (1-6C)alkyl with butyl beingpreferred. Suitable values for Z, suitable catalysts and reactionconditions include those mentioned under (p) above. A particularlysuitable catalyst is, for example, tris(dibenzylidine acetone)palladium0!.

The compounds of formula I in which X is --SCH₂ -- may be be oxidised tothese in which the sulphur atom bears an oxygen atom (that is to a"sulphoxide") using, for example an appropriate quantity of sodiumperiodate. Further oxidation to the compound in which the sulphur atombears two oxygen atoms (that is a "sulphone") may be carried out using aperacid such as peracetic acid or hydrogen peroxide. The oxidation ofsulphur compounds to the corresponding sulphoxides and sulphones is wellknown in the chemical art. Compounds of formula I in which X is --CH₂S-- may be oxidised to the corresponding sulphoxides or sulphones in thesame way.

In some cases oxidation of compounds of formula I to give a sulphone maybe accompanied by some oxidation of the nitrogen atom in thequinuclidine ring to the N-oxide. In such cases the quinuclidine N-oxidemoiety may be reduced back to a quinuclidine moiety without affectingthe sulphone using reducing agents well known in the art, such assulphur dioxide.

It will be appreciated that in some of the reactions mentioned herein itmay be necessary/desirable to protect any sensitive groups in thecompounds. The instances where protection is necessary or desirable andsuitable methods for protection are known to those skilled in the art.Thus, if reactants include groups such as amino, carboxy or hydroxy itmay be desirable to protect the group in some of the reactions mentionedherein. Suitable protecting groups for hydroxy include, for example,silyl groups such as trimethylsilyl or t-butyldimethylsilyl,tetrahydropyranyl and esterifing groups such as a methyl or ethyl ester;and for amino groups include benzyloxycarbonyl and t-butoxycarbonyl.Carboxy groups may be protected in a reduced form such as in the form ofthe corresponding protected alcohol, which may be subsequently oxidisedto give the carboxy group. The protecting groups may be removed at anyconvenient stage in the synthesis using conventional techniques wellknown in the chemical art.

It will also be appreciated that the preferred process for preparing aparticular compound of formula I will depend upon the nature of thevarious radicals. Similarly, the preferred choice of reagent will dependupon the nature of the various radicals present. For example, when it isrequired to reduce a particular compound the reducing agent willgenerally be selected to be one which does not interfere with othergroupings present.

It will also be appreciated that certain of the various optionalsubstituents in the compounds of the present invention may be introducedby standard aromatic substitution reactions or generated by conventionalfunctional group modifications either prior to or immediately followingthe processes mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acylhalide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogeno group. Particularexamples of modifications include the reduction of a nitro group to anamino group by for example, catalytic hydrogenation with a nickelcatalyst or treatment with iron in the presence of hydrochloric acidwith heating; oxidation of alkylthio to alkylsulphinyl oralkylsulphonyl.

It will be appreciated that the substituents on Ar may be reacted, usingstandard chemical methodology, to produce further groups. Thus, forexample, ester groups may be hydrolysed to acid groups which may bereduced to give a hydroxy group. The hydroxy group may then be reactedwith further reagents to give further groups.

In general, it is preferred that the substituents on Ar are introducedbefore Ar is coupled to the quinuclidine moiety but in some instances itmay be appropriate to introduce substituents or modifiy substituentsafter such coupling. The various substituted phenyl derivatives used asstarting materials may, as indicated above, be prepared by methods wellknown in the art. As particular examples starting materials in which Arbears an alkoxy group which may be further substitututed as definedabove may be prepared by alkylation of the appropriate phenol. Thus acompound of formula Hal--Ar--OH may be reacted with a compound offormula R--hal in the presence of a base and a suitable solvent (Hal aresuitable halogen atoms and R represents remainder of the substituent tobe introduced, thus, for example R will be alkoxyalkyl when analkoxyalkoxy substituent is desired. Specific examples illustrating thegeneration of alkoxy substituents further substituted by other groupsare shown in Scheme 3. Compounds in which Ar bears an alkylthio groupwhich may be further substituted may be prepared in an analogous manner.Compounds in which Ar bears an alkoxycarbonylalkyl group may be preparedby esterification of a compound bearing a carboxyalkyl group using theappropriate alcohol and standard conditions such as acid catalysis (eg.sulphuric acid). An alkynyl group (which may be further substituted asdefined above) may be introduced, for example, by reaction of anappropriate compound of formula Ar--Z in which Z is a suitable leavinggroup with a compound of formula HC.tbd.C--R in which R represents theremainder of the substituent in a similar manner to that described in(p) above. In a similar manner compounds with an alkenyl substiuent(which may be further substituted) may be prepared from a compound offormula Ar--Z and R--CH═CH₂. Compounds having an alkenyl substituentsuch as allyl and an oxy substituent may be prepared from a compound offormula ArOH by reaction with, for example, allyl bromide followed by aClaisen rearrangement as illustrated in Scheme 3.

Compounds in which Ar bears a (CH₂)nCO₂ R group in which n is 1 orgreater than 1 and R is, for example, alkyl may be prepared, forexample, by a Wittig reacgtion on the corresponding compound of formulaAr(CH₂)mCOR¹¹ (m=n-1, R¹¹ =H or alkyl) as illustrated in Scheme 4. Theproduct may then be further modified using stand reaction conditons toprovide further desired groups eg. hydrolysed to the acid. Compoundshaving a (CH₂)nCO₂ R group may also be prepared from compounds offormula Ar(CH₂)mCHO (m=n-1) as illustrated in Scheme 4. The acidsprovided may then be further modified by, for example, reduction oresterification to provide further groups or groups which can be reactedfurther.

When a pharmaceutically-acceptable salt of a compound of the formula Iis required, it may be obtained, for example, by reaction of saidcompound with the appropriate acid (which affords a physiologicallyacceptable anion), or with the appropriate base (which affords aphysiologically acceptable cation), or by any other conventional saltformation procedure.

As mentioned previously, the compounds of the formula I (and theirpharmaceutically-acceptable salts) are inhibitors of the enzyme squalenesynthase. Thus the compounds of the present invention are capable ofinhibiting cholesterol biosynthesis by inhibition of de novo squaleneproduction.

The beneficial pharmacological properties of the compounds of thepresent invention may be demonstrated using one or more of the followingtechniques.

(a) Inhibition of Squalene synthase

In this test, the ability of a compound to prevent the formation ofsqualene from a radioactive substrate (tritiated farnesyl pyrophosphate)is assessed.

The test compound is incubated at a concentration of 25 micromolar in200 μl of a buffered solution containing potassium phosphate (50 mM),MgCl₂ (4.95 mM), KF (9.9 mM), NADPH (0.9 mM) and rat liver microsomalprotein (20 μg). Rat liver microsomes are prepared by the methoddescribed in published European Patent Application No. 324,421 andstored in liquid nitrogen prior to assay. Assay vials are kept at 37° C.throughout the incubation.

The reaction is started with the addition of the substrate (1- ³H!-farnesyl pyrophosphate), final concentration 20 μM, and stopped after15 minutes reaction time with the addition of 50 μl of 4% KOH. Thereaction products are separated from unreacted substrate afterapplication to a C-18 octadecyl 1 ccBond column (Analytichem Int productNo. 617101). An aqueous fraction is eluted with 250 μl of 0.1M KOH.Squalene is then eluted with 1.0 ml 10% ethylacetate in hexane andradioactivity determined. The difference in radioactivity in thepresence and absence of the test compound is used to determine the levelof inhibition. If the test compound inhibits at greater than about 70%at 25 micromolar, it is generally re-tested at 25 and 2.5 micromolar.The IC₅₀ (concentration which results in a 50% inhibition of squaleneproduction), of the test compound can be determined by testing thecompound at several, for example five, concentrations predicted from thetwo concentration results. The IC₅₀ can then be determined from a plotof percentage inhibition against concentration of test compound.

In general, compounds of formula I show significant inhibition in theabove test at a concentration in the range of about 0.001 to 25 μM.

By way of illustration of the squalene synthase inhibitory properties ofthe compound of formula I, described in Example 16 below gave aninhibition of about 80% at 2.5 μM.

(b) Acute rat cholesterol synthesis assay.

This is an acute in vivo test in the rat to measure de novo hepaticcholesterol synthesis from exogenously administered ¹⁴ C-acetate.

Female rats (35-55 g) are housed in reverse lighting conditions (redlight from 0200 h-1400 h) for a period of about 2 weeks prior to test.Animals are allowed free access to chow and drinking water throughoutthis period. At test, animals should weigh 125-150 g.

Test compounds may be administered by oral gavage, dissolved orsuspended in 0.5% polysorbate, or by ip or iv dosing. Control animalsreceive vehicle alone. After 1 hour the rats are injected ip with 25 μCi2-¹⁴ C!-acetate (NEN DUPONT. specific activity, 45-60 mCi/mmol NEC-085H,or AHERSHAM specific activity, 50-60 mCi/mmol CFA 14) in a volume of0.25 ml saline (100 μCi/ml). After a further hour, rats are terminallyanaesthetised with halothane and a blood sample obtained from theabdominal vena cava.

1 ml of plasma is lyophilised and then saponified in 2 ml ethanolic KOH(1 part 33% KOH, 9 parts ethanol) at 75° C. for 2 hours. After additionof an equal quantity of water, non-saponifiable lipids are extractedwith two 5 ml volumes of hexane. The hexane extracts are evaporated todryness and the residues dissolved in ethanol to determine cholesterolspecific radioactivity. ED₅₀ values can be determined in the standardway.

In general, compounds of formula I show activity in the range of about0.1 to 100 mg/kg.

By way of illustration, the compound of formula I described in Example16 gave an ED50 of about 5.1 mg/kg.

No overt toxicity was detected when compounds of the formula I wereadministered at several multiples of their minimum inhibitory dose orconcentration.

An alternative test to measure the ability of a compound to inhibitcholesterol synthesis in vivo uses ³ H-mevalonolactone in place of ¹⁴C-acetate.

As mentioned above, the compounds of the present invention are squalenesynthase inhibitors and hence possess the property of inhibitingcholesterol biosynthesis. Thus the compounds of the present inventionwill be useful in treating diseases or medical conditions in which aninhibition of squalene synthase is desirable, for example those in whicha lowering of the level of cholesterol is blood plasma is desirable. Inparticular, the compounds of the present invention will be useful intreating hypercholesterolemia and/or ischaemic diseases associated withatheromatous vascular degeneration such as atherosclerosis. Thecompounds of the present invention will also be useful in treatingfungal infections.

Thus according to a further feature of the present invention there isprovided a method of inhibiting squalene synthase in a warm-bloodedanimals (such as man) requiring such treatment, which method comprisesadministering to said animal an effective amount of a compound offormula I (as herein defined), or a pharmaceutically-acceptable saltthereof. In particular, the present invention provides a method ofinhibiting cholesterol biosynthesis, and more particularly to a methodof treating hypercholesterolemia and atheromatous vascular degeneration(such as atherosclerosis).

Thus the present invention also provides the use of a compound offormula I (as herein defined), or a pharmaceutically-acceptable saltthereof, for the manufacture of a medicament for treating diseases ormedical conditions in which a lowering of the level of cholesterol inblood plasma is desirable (such as hypercholesterolemia andatherosclerosis).

When used in the treatment of diseases and medical conditions in whichan inhibition of cholesterol biosynthesis is desired, for example in thetreatment of hypercholesterolemia or atherosclerosis, it is envisagedthat a compound of formula I (or a pharmaceutically acceptable saltthereof) will be administered orally, intravenously, or by some othermedically acceptable route so that a dose in the general range of, forexample, 0.01 to 50 mg per kg body weight is received. However it willbe understood that the precise dose administered will necessarily varyaccording to the nature and severity of the disease, the age and sex ofthe patient being treated and the route of administration.

In general, the compounds of formula I (or a pharmaceutically-acceptablesalt thereof) will usually be administered in the form of apharmaceutical composition, that is together with a pharmaceuticallyacceptable diluent or carrier, and such a composition is provided as afurther feature of the present invention.

A pharmaceutical composition of the present invention may be in avariety of dosage forms. For example, it may be in the form of tablets,capsules, solutions or suspensions for oral administration, in the formof a suppository for rectal administration; in the form of a sterilesolution or suspension for parenteral administration such as byintravenous or intramuscular injection.

A composition may be obtained by conventional procedures usingpharmaceutically acceptable diluents and carriers well known in the art.Tablets and capsules for oral administration may conveniently be formedwith a coating, such as an enteric coating (for example, one based oncellulose acetate phthalate), to minimise dissolution of the activeingredient of formula I (or a pharmaceutically-acceptable salt thereof)in the stomach or to mask unpleasant taste.

The compounds of the present invention may, if desired, be administeredtogether with (or sequentially to) one or more other pharmacologicalagents known to be useful in the treatment of cardiovascular disease,for example, together with agents such as HMG-CoA reductase inhibitors,bile acid sequestrants, other hypocholesterolaemic agents such asfibrates, for example gemfibrozil, and drugs for the treatment ofcoronary heart disease. As a further example, the compounds of thepresent invention may, if desired, be administered together with (orsequentially to) an angiotensin converting enzyme (ACE) inhibitor, suchas captopril, lisinopril, zofenopril or enalapril.

The invention will now be illustrated by the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo;

(ii) operations were carried out at room temperature, that is in therange 18-26° C.;

(iii) flash column chromatography or medium pressure liquidchromatography (MPLC) was performed on silica gel (Merck KieselgelArt.9385, obtained from E Merck, Darmstadt, Germany);

(iv) yields are given for illustration only and are not necessarily themaximum attainable by diligent process development;

(v) proton NMR spectra were normally determined at 200 MHz in DMSO-d6(unless stated otherwise) using tetramethylsilane (TMS) as an internalstandard, and are expressed as chemical shifts (delta values) in partsper million relative to TMS using conventional abbreviations fordesignation of major peaks: s, singlet; m, multiplet; t, triplet; br,broad; d, doublet;

(vi) all end-products were characterised by microanalysis, NMR and/ormass spectroscopy (molecular ions denoted by m/z values); and

(vii) conventional abbreviations are used for individual radicals andrecrystallisation solvents, for example, Me=methyl, Et=ethyl, Pr=Propyl,Pr^(i) =isopropyl, Bu=butyl, Bu^(i) =isobutyl, Ph=phenyl; EtOAc=ethylacetate, Et₂ O=ether, MeCN=acetonitrile, MeOH=methanol, EtOH=ethanol,Pr^(i) OH=2-propanol, H₂ O=water.

EXAMPLE 1

Bis(triphenylphosphine)-palladium (II) chloride (85 mg) and copper (I)iodide (43 mg) were added to a solution of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate (920 mg) and3-ethynyl-3-hydroxyquinuclidine (375 mg) in dimethyl formamide (5 ml) atambient temperature under an atmosphere of argon. Triethylamine (2.5 ml)was added. The mixture was then stirred for 6 hours at 75° C.

The reaction mixture was cooled to ambient temperature. Water (50 ml)and 2M aqueous sodium carbonate solution (25 ml) were added to themixture and the aqueous phase was extracted with ethyl acetate (3×25ml). The organic phase was filtered. The filtrate was washed with 2Maqueous sodium carbonate solution (1×25 ml) and then with saturatedbrine solution (1×50 ml). The organic phase was dried (MgSO₄) andevaporated to give an oil which was purified by column chromatography onalumina (Alumina 507 C) using a 19:1 (v/v) mixture of ethyl acetate andmethanol as eluent to give an oil. The oil was triturated with hexane togive 3-2-{2-allyl-4-(2-ethoxycarbonylethyl)-phenyl}ethynyl!quinuclidin-3-ol asa solid (270 mg), m.p. 55-6° C.; microanalysis, found: C, 74.6; H, 8.1;N, 3.70%, C₂₃ H₂₉ NO₃.0.1 H₂ O requires: C, 74.8; H, 8.0; N, 3.80%; NMR(CDCl₃): 1.22 (3H, t), 1.35-1.50 (1H, m), 1.58-1.80 (1H, m), 1.90-2.13(3H, m), 2.38-2.57 (1H, m), 2.58 (2H, t), 2.72-2.95 (6H, m), 3.05 (1H,d), 3.30 (1H, d of d), 3.49 (2H, d), 4.12 (2H, q), 4.98-5.10 (2H, m),5.85-6.03 (1H, m), 6.98-7.07 (2H, m) and 7.33 (1H, d); m/z 368 (M+H).

The ethyl 3-(3-allyl 4-trifluoromethylsulphonyloxyphenyl)propionate usedas starting material was obtained as follows.

Allyl bromide (2.30 g) was added to a stirred suspension of ethyl3-(4-hydroxyphenyl)propionate (3.49 g) and anhydrous potassium carbonate(2.76 g) in butan-2-one (30 ml). The reaction mixture was heated atreflux for 18 hours. The reaction mixture was allowed to cool to ambienttemperature and the mixture was filtered. The filtrate was evaporated togive an oil which was purified by column chromatography on silica gel(Merck.Art. No. 9385) using a 4:1 (v/v) mixture of n-hexane and ethylacetate as eluent to give ethyl 3-(4-allyloxyphenyl)propionate (4.09 g)as a colourless oil; NMR (CDCl₃): 1.22 (3H, t), 2.48 (2H, t), 2.88 (2H,t), 4.13 (2H, q), 4.51 (2H, m), 5.25-5.42 (2H, m), 5.95-6.15 (1H, m),6.83 (2H, d) and 7.03 (2H, d); m/z 235 (M+H).

A solution of ethyl 3-(4-allyloxyphenyl)propionate (3 g) in diphenylether (24 ml) was heated at reflux for 12 minutes. The reaction mixturewas allowed to cool to ambient temperature and the reaction mixture wasfiltered through a silica gel pad. Elution with a 4:1 (v/v) mixture ofhexane and ethyl acetate gave slightly impure product. Furtherpurification by medium pressure column chromatography on silica gel(Merck Art. No. 9385) using a 9:1 (v/v) mixture of n-hexane and ethylacetate as eluent gave ethyl (3-allyl-4-hydroxyphenyl)propionate (2.86g) as a yellow oil; microanalysis, found: C, 71.4; H, 7.5%; C₁₄ H₁₈ O₃requires: C, 71.8; H, 7.74%; NMR (CDCl₃): 1.21 (3H, t), 2.58 (2H, m),2.86 (2H, t), 3.37 (2H, d), 4.12 (2H, q), 5.02 (1H, s), 5.07-5.20 (2H,m), 5.90-6.10 (1H, m), 6.67-6.74 (1H, m), 6.90-6.98 (2H, m); m/z 234(M).

Trifluoromethyl sulphonic anhydride (0.93 ml) was added dropwise over 5minutes to a stirred solution of ethyl 3 (3-allyl4-hydroxy)phenyl!propionate (1.17 g) in pyridine (5 ml) at 0° C. underan atmosphere of argon. The mixture was stirred at 0° C. for 16 hoursand then added to ice (50 g). The aqueous mixture was extracted withether (3×30 ml). The ether extracts were combined, washed with water(1×25 ml), 1M aqueous hydrochloric acid (3×25 ml) and saturated brine(2×25 ml). The organic phase was dried (MgSO₄) and evaporated to giveethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate (1.72 g)as an oil; NMR (CDCl₃): 1.22 (3H, t), 2.61 (2H, t), 2.95 (2H, t), 3.45(2H, d), 4.12 (2H, q), 5.06-5.20 (2H, m), 5.83-5.90 (1H, m) and7.05-7.20 (3H, m); m/z 367 (M+H).

The 3-ethynyl-3-hydroxyquinuclidine used as starting material wasobtained as follows:

A solution of n-butyl lithium (100 ml of a 2M solution in pentane) wasadded portion-vise over a period of 20 minutes to a stirred solution ofethynyltrimethylsilane (19.6 g) in dry tetrahydrofuran (400 ml) at -70°C. The mixture was stirred for 1 hour at -70° C. A solution of3-quinuclidinone (2.4 g) in dry tetrahydrofuran (100 ml) was then addedto the mixture and the mixture stirred for 1 hour at -70° C. Methanol (1ml) was then added to the mixture and the mixture allowed to warm toroom temperature. The solvents were removed by evaporation. Methanol(500 ml) and potassium carbonate (40 g) were added to the residue andthe mixture was stirred for 1 hour. The solvent was removed byevaporation. The residue was triturated with water (500 ml) and thendried in vacuo to give 3-ethynyl-3-hydroxy-quinuclidine as a solid, m.p.193-197° C.; NMR (DMSO-d₆): 1.5-1.3(1H, m), 1.4-1.6(1H, m), 1.7-1.95(3H,m), 2.55-2.8(5H, m), 2.95(1H, d), 3.3(1H, d) and 5.4(1H, s); m/z 152(M+H).

EXAMPLE 2

Using the method described in Example 1, but with ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)acetate in place of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate, there wasthus obtained 3-2-(2-allyl-4-ethoxycarbonylmethylphenyl)ethynyl!quinuclidin-3-ol as asolid, mp 84-6° C.; microanalysis, found: C, 72.8; H, 7.60; N, 3.40%;C₂₂ H₂₇ NO₃ 0.5 H₂ O requires C, 72.9; H, 7.60; N, 3.80%; NMR (CDCl₃)1.25 (3H, t), 1.38-1.55 (1H, m), 1.60-1.78 (1H, m), 1.90-2.18 (3H, m),2.20-2.50 (1H, m), 2.73-3.00 (4H, m), 3.08 (1H, d), 3.35 (1H, d), 3.51(2H, d), 3.58 (2H, s), 4.14 (2H, q), 5.0-5.10 (2H, m), 5.85-6.05 (1H,m), 7.07 (2H, m) and 7.35 (1H, d); m/z 354 (M+H).

The ethyl 3-(3-allyl 4-trifluromethylsulphonyloxyphenyl)acetate used asstarting material was prepared from ethyl(2-allyl-4-hydroxyphenyl)acetate using the method described in Example 1for the preparation of ethyl-3- (3-allyl-4-hydroxy)phenyl!-propionate.There was thus obtainedethyl-3-(3-allyl-4-trifluromethylsulphonyloxyphenyl)acetate as an oil;NMR (CDCl₃): 1.25 (3H, t), 3.45 (2H, d), 3.61 (2H, s), 4.15 (2H, q),5.08-5.18 (2H, m), 5.82-5.97 (1H, m) and 7.25 (3H, m); m/z 353 (M+H).

The ethyl (3-allyl-4-hydroxyphenyl)acetate was obtained using the methodin Rec. Trav. Pays Bas, 1952, 71, 879).

EXAMPLE 3

Using the method described in Example 1, but with ethyl(3-allyl-4-trifluoromethylsulphonyloxyphenyl)oxyacetate in place ofethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate, therewas thus obtained 3-2-(2-allyl-4-ethoxycarbonylmethyloxyphenyl)-ethynyl!quinuclidin-3-ol asa solid, mp 98-99° C.; microanalysis, found: C, 69.9; H, 7.30; N, 3.80%;C₂₂ H₂₇ NO₄ 0.5 H₂ O requires C, 70.0; H, 7.40; N, 3.70%; NMR (CDCl₃):1.30 (3H, t), 1.35-1.52 (1H, m), 1.60-1.75 (1H, m), 1.92-2.15 (3H, m),2.15-2.45 (1H, m), 2.70-2.95 (4H, m), 3.07 (1H, d), 3.32 (1H, d of d),3.51 (2H, d), 4.26 (2H, q), 4.60 (2H, s), 5.0-5.12 (2H, m), 5.86-6.02(1H, m), 6.65-6.75 (2H, m) and 7.35 (1H, d); m/z 370 (M+H).

The ethyl (3-allyl-4-trifluoromethylsulphonyloxyphenyl)oxyacetate usedas starting material, was prepared as follows.

Allyl bromide (3.37 g) was added to a stirred suspension of ethyl4-hydroxyphenoxyacetate (5.14 g) prepared by method of Moser, J.A.C.S.,(1950), 72, 1413) and potassium carbonate (3.90 g) in butan-2-one (50ml). The reaction mixture was heated at reflux for 12 hours. Thereaction mixture was cooled to ambient temperature and then filtered.The filtrate was evaporated to give an oil which was purified by columnchromatography on silica gel (Merck. Art. No. 7734) using a 4:1 (v/v)mixture of hexane and ethylacetate as eluent to give ethyl4-allyloxyphenoxyacetate (6.41 g) as a colourless oil; microanalysis,found: C, 65.8; H, 7.20%; C₁₃ H₁₆ O₄ requires C, 66.1; H, 6.83%; NMR(CDCl₃): 1.28 (3H, t), 4.25 (2H, q), 4.48 (2H, m), 4.57 (2H, s),5.22-5.44 (2H, m), 5.92-6.12 (1H, m) and 6.84 (4H, s).

A solution of ethyl 4-allyloxyphenoxyacetate (2.0 g) in diphenylether(15 ml) was heated at reflux for 12 minutes. The reaction mixture wasallowed to cool to ambient temperature and the reaction mixture waspoured onto a silica gel pad (Merck Art. No. 9385). Elution with hexanefollowed by a 4:1 (v/v) mixture of hexane and ethyl acetate gave ethyl3-allyl-4-hydroxyphenoxyacetate (1.62 g) as a solid, mp 52.8° C.;microanalysis, found: C, 66.3; H, 7.20%; C₁₃ H₁₆ O₄ requires: C, 66:1;H, 6.83%; NMR (CDCl₃): 1.28 (3H, t), 3.35 (2H, d), 4.25 (2H, q), 4.55(2H, s), 4.73 (1H, s), 5.07-5.20 (2H, m), 5.88-6.10 (1H, m) and6.62-6.78 (3H, m); m/z 237 (M+H).

The method described in Example 1 for the preparation of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate was used toconvert ethyl 3-allyl-4-hydroxyphenoxyacetate to ethyl(3-allyl-4-trifluoromethylsulphonyloxyphenyl)oxyacetate as a colourlessoil, NMR (CDCl₃) 1.27 (3H, t), 3.42 (2H, d), 4.25 (2H, q), 4.60 (2H, s),5.07-5.20 (2H, m), 5.80-5.97 (1H, m), 6.72-6.85 (2H, m) and 7.15 (1H,d); m/z 368 (M).

EXAMPLE 4

A mixture of ethyl 2-allyl-4-bromophenoxyacetate (912 mg),3-ethynyl-3-hydroxyquinuclidine (453 mg), bis(triphenylphosphine)-palladium (II) chloride (106 mg), copper (I) iodide(53 mg), triethylamine (3 ml) and dimethylformamide (6 ml) was stirredat 80° C. under an atmosphere of argon for 8 hours. The reaction mixturewas cooled to ambient temperature and water (100 ml) was added. Themixture was extracted with ethyl acetate (3×50 ml). The ethyl acetateextracts were combined and filtered. The filtrate was washed withsaturated brine solution (3×50 ml), dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography on Alumina (Fluka 507C)using ethyl acetate containing 2.5% methanol as eluent to give 3-2-(3-allyl-4-ethoxycarbonylmethyloxyphenyl)ethynyl!quinuclidin-3-ol (220mg) as a solid, mp 95.9° C.; microanalysis, found: C, 70.7; H, 7.30; N,3.50%; C₂₂ H₂₇ NO₄.0.25 H₂ O requires: C, 70.6; H, 7.35; H, 3.72%; NMR(CDCl₃): 1.28 (3H, t), 1.34-1.47 (1H, m), 1.52-1.72 (1H, m), 1.90-2.25(3H, m), 2.25-2.60 (1H, m), 2.62-2.92 (4H, m), 2.97-3.09 (IH, d),3.25-3.35 (1H, d of d), 3.42 (2H, d), 4.26 (2H, q), 4.62 (2H, s),5.02-5.15 (2H, m), 5.88-6.08 (1H, m), 6.60-6.68 (1H, m) and 7.17-7.27(2H, m); m/z 370 (M+H).

The ethyl 2-allyl-4-bromophenoxyacetate was prepared as follows.

Ethyl bromoacetate (1.68 g) was added to a stirred suspension of2-allyl-4-bromophenol (2.13 g) and potassium carbonate (1.50 g) inbutan-2-one (15 ml). The mixture was heated at reflux for 16 hours. Thereaction mixture was cooled to ambient temperature and filtered. Water(100 ml) was added to the filtrate and the aqueous phase was extractedwith ethyl acetate (3×50 ml). The ethyl acetate extracts were combined,washed with brine (2×25 ml), dried (MgSO₄) and evaporated to give asolid which crystallised from hexane to give ethyl2-allyl-4-bromophenoxyacetate (2.10 g), mp 70.5° C.; microanalysis,found: C, 52.0; H, 5.10%; C₁₃ H₁₅ BrO₃ requires: C, 52.2; H, 5.05%; NMR(CDCl₃) 1.29 (3H, t), 3.42 (2H, d), 4.25 (2H, q), 4.58 (2H, s),5.07-5.17 (2H, m), 5.88-6.18 (1H, m), 6.60 (1H, d) and 7.20-7.27 (2H,m); m/z 300 (M+H).

The 2-allyl-4-bromophenol was prepared by the method of Claisen andEisleb, Annalen, 401, 1913, 38.

EXAMPLE 5

Using the method described in Example 4, but with ethyl4-bromophenoxyacetate in place of ethyl 2-allyl-4-bromophenoxyacetate,there was thus obtained 3-2-(4-ethoxycarbonylmethyloxyphenyl)ethynyl!quinuclidin-3-ol as a solid,mp 137.1° C.; microanalysis, found: C, 69.6; H, 7.40; N, 4.1%; C₁₉ H₂₃NO₄ requires: C, 69.3; H, 7.04; N, 4.25%; NMR (CDCl₃): 1.27 (3H, t),1.33-1.52 (1H, m), 1.54-1.77 (1H, m), 1.90-2.18 (3H, m), 2.20-2.70 (1H,m), 2.72-2.97 (4H, m), 3.03 (1H, d), 3.31 (1H, d of d), 4.21 (2H, q),4.60 (2H, s), 6.78-6.88 (2H, d) and 7.30-7.40 (2H, d); m/z 330 (M+H).

The starting ethyl 4-bromophenoxyacetate was prepared by the method ofAdams and Powell, J.A.C.S. 42, 1920, 656.

EXAMPLE 6

Using the method described in Example 4, but with ethyl 4-bromophenylacetate in place of ethyl-2-allyl-4-bromophenoxyacetate, there was thusobtained 3- 2-(4-ethoxycarbonylmethylphenyl)ethynyl!quinuclidin-3-ol asa solid, mp 132.5° C.; microanalysis: C, 72.6; H, 7.60; N, 4.30%; C₁₉H₂₃ NO₃ requires: C 72.8; H 7.40; N, 4.47%; NMR ( CD₃ !₂ SO): 1.18 (3H,t), 1.30 (1H, m), 1.59 (1H, m), 1.75-2.00 (3H, m), 2.67 (4H, t), 2.81(1H, d), 3.07 (1H, d), 3.68 (2H, s), 4.08 (2H, q), 5.55 (1H, s) and7.20-7.40 (4H, q); m/z 314 (M+H).

EXAMPLE 7

A mixture of 4-(2-methoxyethoxy)-iodobenzene (13.9 g),3-ethynyl-3-hydroxyquinuclidine (7.55 g),bis(triphenylphosphine)palladium (II) chloride (1.75 g), copper (I)iodide (875 mg), triethylamine (25 ml) and dimethylformamide (50 ml) wasstirred under an atmosphere of argon when an initial exothermic reactionensued, the reaction temperature rising to 50° C. The reaction mixturewas then stirred at ambient temperature for a further 16 hours. Thetriethylamine and dimethylformamide were removed by evaporation. Theresidue was dissolved in dichloromethane (500 ml) and washed with a 2Maqueous sodium hydroxide solution (2×50 ml), water (50 ml), dried(MgSO₄) and evaporated. The residue was purified by flash columnchromatography on silica gel (Merck Art. No. 9385) using a gradient of5% methanol in dichloromethane containing 1% 0.880 ammonia to 10%methanol in dichloromethane containing 1% 0.880 ammonia as eluent togive a solid (15 g). This solid was further purified by crystallisationfrom acetonitrile to give 3-2-{4-(2-methoxyethoxy)phenyl}ethynyl!quinuclidin-3-ol (7.2 g) as a solidmp 148°-149° C.; microanalysis; found C 71.9; H 7.9; N 4.6%; C₁₈ H₂₃ NO₃requires: C 71.7; H 7.69; N 4.65%; NMR ( CD₃ !₂ SO): 1.2-1.35 (1H, m),1.5-1.65 (1H, m), 1.78-1.97 (3H, m), 2.6-2.73 (4H, m), 2.75-2.85 (1H,d), 2.99-3.09 (1H, d), 3.3 (3H, s), 3.6-3.68 (2H, m), 4.05-4.13 (2H, m),5.46 (1H, br), 6.88-6.95 (2H, d) and 7.28-7.35 (2H, d); m/z 302 (M+H).

The 4-(2-methoxyethoxy)iodobenzene used as starting material wasobtained as follows.

A mixture of 4-iodophenol (20 g), 2-bromoethylmethyl ether (11.4 g),potassium carbonate (12.5 g) and dimethylformamide (100 ml) was stirredat 80° C. for 4 hours. A further portion of 2-bromoethylmethyl ether(2.24 g) and potassium carbonate (2.5 g) was then added and the mixturestirred at 80° C. for a further 1 hour. The dimethylformamide wasremoved by evaporation. The residue was treated with a 2M aqueous sodiumhydroxide solution (50 ml) and the mixture extracted with diethyl ether(3×50 ml). The ethereal extracts were combined, washed with 2M aqueoussodium hydroxide solution (2×20 ml), brine (20 ml), dried (MgSO₄) andevaporated to give 4-(2-methoxyethoxy)iodobenzene (23 g) as a whitesolid, m.p. 36-37° C. NMR ( CD₃ !₂ SO): 3.3 (3H, s), 3.6-3.7 (2H, m),4.0-4.1 (2H, m), 6.72-6.82 (2H, d) and 7.52-7.62 (2H, d).

EXAMPLE 8

A 1M solution of lithium aluminium hydride in tetrahydrofuran (10 ml)was added over a period of 20 minutes to a stirred solution of 3-2-{4-(2-methoxyethoxy)phenyl}ethynyl!quinuclidin-3-ol (3.01 g) in drytetrahydrofuran (100 ml) under an atmosphere of argon at 40° C. Thereaction mixture was then stirred at ambient temperature for 16 hours.Water (0.4 ml) and 2M aqueous sodium hydroxide solution (0.8 ml) wasthen added to the reaction mixture dropwise followed by a furtherquantity of water (1.2 ml). The resulting precipitate was collected byfiltration and the filtrate was evaporated. The residue from thefiltrate was crystallised from acetonitrile to give 3-(E)-2-{4-(2-methoxyethoxy)phenyl}vinyl!quinuclidin-3-ol (2.54 g) as asolid, mp 164-166° C., microanalysis, found C,71.4; H,8.6; N,4.5%; C₁₈H₂₅ NO₃ requires: C,71.3; H,8.31; N,4.62%; NMR ( CD₃ !₂ SO): 1.15-1.32(1H, m), 1.38-1.52 (1H, m), 1.62-1.74 (2H, m), 1.95-2.1 (1H, m),2.58-2.6 (5H, m), 2.82-2.92 (1H, d), 3.3 (3H, s), 3.6-3.67 (2H, m),4.03-4.1 (2H, m), 4.66 (1H, s), 6.38-6.45 (1H, d, J=16.67), 6.51-6.58(1H, d, J=16.67), 6.86-7.12 (2H, d) and 7.32-7.38 (2H, d); m/z 304(M+H).

EXAMPLE 9

A mixture of 3- 2-{4-(2-methoxyethoxy)phenyl}ethynyl!-quinuclidin-3-ol(1.8 g) in ethanol (200 ml) and a catalyst of 10% (v/v) palladium oncarbon (100 mg) was stirred under an atmosphere of hydrogen untilhydrogen uptake ceased. The palladium/carbon catalyst was removed byfiltration and the filtrate was evaporated. The residue was crystallisedfrom a 3:1 (v/v) mixture of cyclohexane ethylacetate to give 3-2-{4-(2-methoxyethoxy)phenyl}ethyl!quinuclidin-3-ol (700 mg) as a solid,mpt 116-117° C. Microanalysis, found C,71.1; H,9.2; N,4.5%; C₁₈ H₂₇ NO₃requires: C,70.8; H,8.9; N,4.59%; NMR ( CD₃ !₂ SO): 1.15-1.35 (1H, m),1.4-1.6 (1H, m), 1.65-1.78 (2H, m), 1.9-2.08 (1H, m), 2.45-2.8 (10H, m),3.3 (3H, s), 3.6-3.68 (2H, m), 4.0-4.08 (2H, m), 4.3 (1H, br), 6.78-6.86(2H, d), 7.05-7.13 (2H, d); m/z 306 (M+H).

EXAMPLE 10

Bis(triphenylphosphine)-palladium (II) chloride (95 mg) was added to astirred mixture of 3-ethynyl-3-hydroxyquinuclidine (400 mg),

1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane (704 mg) and copper (I)iodide (48 mg) in dimethylformamide (DMF) (5.5 ml) and triethylamine(2.7 ml) at ambient temperature and under an atmosphere of argon. Themixture was heated at 65° C. for 14 hours, cooled to ambienttemperature, diluted with 2M aqueous sodium hydroxide (20 ml) andextracted with diethyl ether (5×100 ml). The ethereal extracts werecombined, washed with water (100 ml) and saturated brine (100 ml), dried(K₂ CO₃) and evaporated. The residue was crystallised from acetonitrileto give 3-2-(4-{2-methoxyethoxy}-3,5-dimethylphenyl)ethynyl!quinuclidin-3-ol (130mg) as a solid, m.p. 120° C.; microanaylsis, found: C, 72.4; H, 8.2; N,4.1%; C₂ OH₂₇ NO₃ requires: C, 72.9; H, 8.3; N, 4.2%; NMR( CD₃)₂ SO):1.3(1H,m), 1.57(1H,m), 1.9(3H,m), 2.21(6H,s), 2.65(4H,m), 2.8(1H,d),3.02(1H,d), 3.31(3H,s), 3.61(2H,m), 3.87(2H,m), 5.5(1H,br) and7.07(2H,s); m/z 330 (M+H).

The 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane used as startingmaterial was obtained as follows.

Lithium hydride (200 mg) was added to a stirred solution of4-bromo-2,6-dimethylphenol (65 g) in DMF at ambient temperature. Whenevolution of hydrogen had ceased, ethylene carbonate (31.9 g) was addedand the mixture was heated at 150° C. for 12 hours. The DMF was removedby evaporation and the cooled residue was dissolved in ethyl acetate(500 ml). The ethyl acetate solution was washed with water (2×100 ml)and then with saturated brine (100 ml), dried (MgSO₄) and evaporated.The residue was crystallised from methanol to give2-(4-bromo-2,6-dimethylphenoxy)ethanol (51 g), m.p. 47-48° C. NMR(CDCl₃): 2.21(6H,s), 3.86(2H,m), 3.93(2H,m), 7.12(2H,s).

A solution of 2-(4-bromo-2,6-dimethylphenoxy)ethanol (15 g) in methylenechloride (100 ml) was added to a stirred solution of sodium hydroxide(50 g) in water (50 ml) at 5° C. Dimethyl sulphate (8.6 ml) was addeddropwise to the stirred solution at 5° C. over 30 minutes. The mixturewas stirred at ambient temperature for 12 hours. Dimethylsulphate (5 ml)was added at ambient temperature and the mixture stirred for a further 2hours. The mixture was cooled to 0° C. and a solution of ammonia (10 ml,density=0.88 g/cm³) was added. The mixture was stirred for 20 minutes,diluted with iced water (500 ml). The methylene chloride phase wasremoved and the aqueous phase extracted with methylene chloride (2×150ml). The organic extracts were combined, washed with water (2×100 ml),saturated brine (100 ml) and evaporated. The residue was distilled usinga short path distillation apparatus (furnace temperature 120° C./0.08bar) to give 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane (11.6 g);NMR(CDCl₃): 2.34(6H,s), 3.52(3H,s), 3.78(2H,m), 3.96(2H,m) and7.2(2H,s).

EXAMPLE 11

Using the procedure described in Example 10, but using1-(4-bromobenzyloxy)-2-methoxyethane in place of1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane, there was thus obtained3- 2-(4-{2-methoxyethoxymethyl}phenyl)ethynyl!quinuclidin-3-ol (14%) asa solid, m.p. 127-128° C.; microanalysis, found: C, 71.9; H, 7.8; N,4.4%; C₁₉ H₂₅ NO₃ requires: C, 72.4; H, 8.0; N, 4.4%; NMR ( CD₃ !₂ SO):1.30(1H,m), 1.61(1H,m), 1.95(3H,m), 2.69(4H,t), 2.83(1H,d), 3.07(1H,d),3.25(3H,s), 3.49(2H,m), 3.56(2H,m), 4.50(2H,s), 5.58(1H,br), 7.30(2H,d)and 7.39(2H,d); m/z 316 (M+H).

The 1-(4-bromobenzyloxy)-2-methoxyethane used as starting material wasobtained as follows.

2-Methoxyethanol (5.0 g) was added to a stirred suspension of sodiumhydride (2.64 g of a 60% mineral oil suspension) in DMF (200 ml) atambient temperature and under an atmosphere of argon. The stirredmixture was heated to 60° C. and then cooled to 5° C. Solid4-bromobenzyl bromide (15 g) was added in one portion. The mixture wasstirred for 12 hours at ambient temperature, then for 1 hour at 60° C.and cooled. The mixture was diluted with iced water (600 ml) andextracted with ethyl acetate (3×200 ml). The ethyl acetate extracts werecombined, washed with 2M aqueous hydrochloric acid (100 ml), water(2×100 ml), saturated brine (100 ml), dried (MgSO₄) and evaporated. Theresidue, an oil, was distilled using a short path distillation apparatus(furnace temperature 125° C./0.05 bar) to give1-(4-bromobenzyloxy)-2-methoxyethane (9.8 g); NMR (CDCl₃): 3.39(3H,s),3.51(4H,m), 4.51(2H,s), 7.21(2H,d) and 7.44(2H,d).

EXAMPLE 12

Using a similar procedure to that described in Example 10, but using1-(4-bromophenoxy)-2-methoxy-1-methoxymethylethane as starting materialin place of 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane, there wasobtained 3-2-(4-{2-methoxy-1-methoxymethylethoxy}phenyl)ethynyl!quinuclidin-3-ol(33% yield) as a solid, m.p. 125-127° C. (after recrystallisation fromacetonitrile); microanalysis, found C, 69.6; H, 8.0, N, 4.0%; C₂₀ H₂₇NO₄ requires: C, 69.5; H, 7.9; N, 4.1%; NMR( CD₃ !₂ SO): 1.2-1.4(1H,m),1.5-1.65(1H,m), 1.7-2.0(3H,m), 2.6-2.75(4H,t), 2.75-2.9(1H,d),3.0-3.1(1H,d), 3.25(6H,s), 3.5-3.6(4H,d), 4.55-4.7(1H,m), 5.5(1H,s),6.9-7.0(2H, and 7.25-7.35(2H,d); m/z 346(M+H).

The 1-(4-bromophenoxy)-2-methoxy-1-methoxymethylethane used as astarting material was obtained using a similar procedure to thatdescribed for the preparation of the starting material in Example 14,but starting from 4-bromophenol and 1,3-dimethoxypropan-2-ol (obtainedas described in JACS 1939, 61, 433). There was thus obtained1-(4-bromophenoxy)-2-methoxy-1-methoxymethylethane; NMR(CDCl₃):3.4(6H,s), 3.6(4H,s), 4.4-4.5(1H,m), 6.8-6.9(2H,d) and 7.3-7.4(2H,d).

EXAMPLE 13

Using a similar procedure to that described in Example 10, but using1-(4-bromo-2,6-dimethylphenoxy)-2-ethoxyethane as starting material inplace of 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane, there wasobtained 3-2-(4-{2-ethoxyethoxy}-3,5-dimethylphenyl)ethynyl!quinuclidin-3-ol (36%yield) as a solid, m.p. 113-115° C. (after recrystallisation fromacetonitrile); microanalysis, found C, 73.1; H, 8.6, N, 4.4%; C₂₁ H₂₉NO₃ requires: C,73.4; H, 8.5; N, 4.1% NMR(CDCl₃) 1.2-1.3(3H,t),1.3-1.5(1H,m), 1.5-1.7(1H,m), 1.9-2.2(3H,m), 2.25(6H,s),2.75-2.95(4H,t), 2.95-3.05(1H,d), 3.2-3.4(1H,d of d), 3.5-3.7(2H,q),3.7-3.8(2H,q), 3.9-4.0(2H,q) and 7.1(2H,s); m/z 344(M+H).

The 1-(4-bromo-2,6-dimethylphenoxy)-2-ethoxyethane used as startingmaterial was obtained in an analogous manner to that for the preparationof 1-(4-bromo-2,6-dimethylphenoxy-2-methoxy ethane in Example 10 butusing diethylsulphate as the alkylating reagent. There was thus obtained1-(4-bromo-2,6-dimethylphenoxy)-2-ethoxyethane, NMR(CDCl₃):1.2-1.3(3H,t), 2.25(6H,s), 3.55-3.65(2H,q), 3.7-3.8(2H of d),3.85-3.95(2H,d of d) and 7.15(2H,s).

EXAMPLE 14

Using a similar procedure to that described in Example 10, but using1-(4-bromo-2,6-dimethylphenoxy)-2-phenoxyethanol as starting material inplace of 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane and extractingthe aqueous mixture obtained after diluting the reaction mixture with 2Maqueous sodium hydroxide with dichloromethane instead of diethyl ether,there was obtained 3-2-(4-{2-phenoxyethoxy}-3,5-dimethylphenyl)ethynyl!quinuclidine-3-ol (28%yield) as a solid, m.p. 141-142° C. (after recrystallisation fromacetonitrile); microanalysis, found: C, 76.2; H, 7.4; N, 3.5%; C₂₅ H₂₉NO₃ requires: C, 76.7, H, 7.5; N, 3.6%; in 28% yield NMR ( CD₃ !₂ O):1.2-1.4(1H,m), 1.5-1.65(1H,m), 1.7-2.0(3H,m), 2.15-2.3(6H,s),2.6-2.75(4H,t), 2.75-2.9(1H,d), 2.95-3.1(1H,d), 4.0-4.3(4H,m),5.5(1H,s), 6.9-7.05(3H,m), 7.1(2H,s) and 7.25-7.4(2H,m); m/z 392 (M+H).

The 1-(4-bromo-2,6-dimethylphenoxy)-2-phenoxyethane used as a startingmaterial was obtained as follows.

A solution of diethyl azodicarboxylate (3.5 g) in tetrahydrofuran (5 ml)was added portionvise over a period of 30 minutes to a stirred solutionof triphenylphosphine (5.2 g), phenol (1.88 g) and2-(4-bromo-2,6-dimethylphenoxy)ethanol in dry tetrahydrofuran (30 ml)under an atmosphere of argon at 0° C. The resultant mixture was allowedto attain ambient temperature and stirred for a further 18 hours. Thetetrahydrofuran was removed by evaporation and the residue was purifiedby flash column chromatography on silica gel (Merck Art No. 9385) using5% ethyl acetate/hexane as eluent to give1-(4-bromo-2,6-dimethylphenoxy)2-phenoxyethane (1.07 g) as a solid, m.p.49-50° C. (after recrystallisation from hexane).

EXAMPLE 15

Using a similar procedure to that described in Example 10, but using1-(4-bromophenoxy)-2-phenoxyethane as starting material in place of1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane and extracting theaqueous mixture obtained after diluting the reaction mixture with 2Maqueous sodium hydroxide with dichloromethane instead of diethyl ether,there was obtained 3-2-(4-{2-phenoxyethoxy}phenyl)ethynyl!quinuclidin-3-ol (18% yield) as asolid, m.p. 207-208° C. (after recrystallisation from acetonitrile);microanalysis, found: C,74.7; H, 6.9; N, 3.8% C₂₃ H₂₄ NO₃. 0.3H₂ Orequires: C, 74.9; H, 7.0; N, 3.8%; NMR ( CD₃ !₂ SO): 1.2-1.4(1H,m),1.5-1.65(1H,m), 1.7-2.0(3H,m), 2.55-2.75(4H,t), 2.75-2.9(1H,d),3.0-3.15(1H,d), 4.2-4.4(4H,m), 5.5(1H,s), 6.9-7.05(5H,m) and7.2-7.4(4H,m); m/z 364 (M+H).

The 1-(4-bromophenoxy)-2-phenoxyethane (m.p. 101-102° C.) used as astarting material was obtained in a similar manner to that for thepreparation of 1-(4-bromo-2,6-dimethylphenoxy)-2-phenoxyethane describedin Example 15, but using 2-(4-bromophenoxy)ethanol and phenol asstarting materials.

EXAMPLE 16

Using a similar procedure to that described in Example 10, but using1-(4-bromo-3,5-dimethylphenoxy)-2-methoxyethane as starting material inplace of 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane, there wasobtained 3-2-(4-{(2-methoxyethoxy}-2,6-dimethylphenyl)ethynyl!quinuclidin-3-ol (7%yield) as a solid, m.p. 140-142° C. (after recrystallisation fromacetonitrile); microanalysis, found: C, 72.8; H, 8.1, N, 4.4%; C₂₀ H₂₇NO₃ requires: C, 72.9; H, 8.3; N, 4.3%; NMR ( CD₃ !₂ SO): 1.2-1.4(1H,m),1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.3(6H,s 2.6-2.8(4H,m), 2.8-3.0(1H,d),3.05-3.2(1H,d), 3.25(3H,s), 3.6-3.7(1H,d of d), 4.0-4.1(1H,d of d)5.5(1H,s) and 6.65(2H,s); m/z 330 (M+H).

The 1-(4-bromo-3,5-dimethylphenoxy)-2-methoxyethane used as startingmaterial was obtained in an analogous manner to that for the preparationof 3-(4-bromo-2,6-dimethylphenoxy)tetrahydrofuran described in Example14, but using 4-bromo-3,5-dimethylphenol and 2-methoxyethanol asstarting materials. There was thus obtained1-(4-bromo-3,5-dimethylphenoxy)-2-methoxyethane; NMR(CDCl₃): 2.4(6H,s),3.4(3H,s), 3.65-3.75(2H,m), 4.0-4.1(2H,m) and 6.65(2H,s)

EXAMPLE 17

A mixture of 3-ethynyl-3-hydroxyquinuclidine (574 mg), methoxyethyl2-methoxyethoxy-5-iodobenzoate (1.6 g), bis(triphenylphosphine)palladium(II) chloride (135 mg), copper (I), iodide (75 mg), triethylamine (5 ml)and dimethylformamide (10 ml) was stirred at 70° C. under an atmosphereof argon for 2 hours. The triethylamine and dimethylformamide wereremoved by evaporation. The residue was purified by flash columnchromatography on silica gel (Merck Art No 9385) using a mixture of 3%triethylamine in ethyl acetate as eluent to give, after trituration withdichloromethane/pentane (1:1, 10 ml), 3-2-(4-(2-methoxyethoxy)-3-(2-methoxyethoxycarbonyl)phenyl)ethynyl!quinuclidin-3-ol(350 mg) as a colourless solid, m.p. 100-102° C.; microanalysis, found:C, 65.7; H, 7.4; N, 3.4%; C₂₂ H₂₉ NO₆ requires: C,65.5; H, 7.2; N, 3.5%;NMR ( CD₃ !₂ SO): 7.6(1H,d), 7.5(1H, d of d), 7.2(1H,d), 5.5(1H,s),4.3(2H,m), 4.2(2H,m), 3.7-3.6(4H,m), 3.32(3H,s), 3.30(3H,s), 2.9(2H,m),2.7(4H,m), 2-1.8(3H,m), 1.6(1H,m), 1.3(1H,m); m/z 404 (M+H).

The methoxyethyl 2-methoxyethoxy-5-iodobenzoate used as startingmaterial was obtained as follows.

A mixture of 2-hydroxy-5-iodobenzoic acid (1.32 g), bromoethyl methylether (1.39 g), potassium carbonate (1.5 g) and dimethylformamide (10ml) was stirred at 70° C. under an atmosphere of argon for 14 hours. Themixture was cooled to ambient temperature, diluted with water (10 ml)and extracted with ethyl acetate (100 ml). The organic extract waswashed with aqueous sodium carbonate solution, dilute aqueoushydrochloric acid, water and saturated brine and dried (MgSO₄).Evaporation gave methoxyethyl 2-methoxyethoxy-5-iodobenzoate (1.64 g) asa yellow oil; NMR ( CD₃ !₂ SO): 7.7(2H,m), 6.9(1H,d), 4.2(2H,m),4.0(2H,m), 3.5(4H,m), 3.20(3H,s) and 3.19(3H,s); m/z 380(H).

EXAMPLE 18

A mixture of 3-ethynyl-3-hydroxyquinuclidine (453 mg), methoxyethyl4-bromo-2-chlorophenyl ether (0.97 g), bis(triphenylphosphine)palladium(II) chloride (105 mg), copper (I) iodide (55 mg), triethylamine (5 ml)and dimethylformamide (10 ml) was stirred at 70° C. under an atmosphereof argon for 2 hours. The triethylamine and dimethylformamide wereremoved by evaporation. The residue was purified by flash columnchromatography on silica gel (Merck Art. No. 9385) using a mixture of10% methanol in dichloromethane containing 1% ammonia (density, 0.880g/cm³) as eluent. The residue was crystallised from acetonitrile to give3- 2-(3-chloro-4-(2-methoxyethoxy)phenyl)ethynyl!quinuclidin-3-ol (0.52g) as a colourless solid, m.p. 138-139° C.; microanalysis, found: C,64.1; H, 6.7; N, 4.1%; C₁₈ H₂₂ ClNO₃ requires: C, 63.9; H, 6.6; N, 4.1%;NMR ( CD₃ !₂ SO): 7.5(1H,d), 7.3(1H,d of d), 7.1(1H,d), 5.5(1H,s),4.2(2H,m), 3.7(2H,m), 3.3(3H,s), 2.8(2H,m), 2.7(4H,m), 2-1.8(3H,m),1.6(1H,m) and 1.3(1H,m); m/z 336(M+H).

The methoxyethyl 4-bromo-2-chlorophenyl ether used as starting materialwas obtained as follows.

A mixture of 4-bromo-2-chlorophenol (1.04 g) bromoethyl methyl ether(0.70 g), potassium carbonate (0.76 g) and dimethylformamide (5 ml) wasstirred at 70° C. under an atmosphere of argon for 14 hours. The mixturewas cooled to ambient temperature, diluted with water (100 ml) andextracted with ethyl acetate (100 ml). The organic extract was washedwith aqueous sodium carbonate, saturated brine and dried (MgSO₄).Evaporation gave methoxyethyl 4-bromo-2-chlorophenyl ether (1.14 g) as acolourless oil; NMR ( CD₃ !₂ SO): 7.7(1H,d), 7.5(1H,dd), 6.9(1H,d),4.2(2H,m), 3.7(2H,m) and 3.3(3H,s); m/z 264/266 (M+H).

EXAMPLE 19

A mixture of 2-benzyl-1-phenyltrifluoromethane sulphonate (1.27 g),3-ethynyl-3-hydroxyquinuclidine (604 mg),bis(triphenylphosphine)-palladium (II) chloride (140 mg), copper (I)iodide (70 mg), triethylamine (4 ml) and dimethylformamide (8 ml) wasstirred at 70° C. under an atmosphere of argon for 3 hours. Thetriethylamine and dimethylformamide were removed by evaporation. A 2Maqueous solution of sodium hydroxide (25 ml) was added to the residueand the mixture extracted with dichloromethane. The organic extractswere combined, washed with water and saturated brine, dried (MgSO₄) andevaporated. The residue was purified by flash column chromatography onsilica gel (Merck Art 9385) using 10% methanol in dichloromethanecontaining 1% ammonia (density, 0.880 g/cm³) as eluent to give (afterre-crystallisation from acetonitrile) 3-2-(2-benzylphenyl)ethynyl!quinuclidin-3-ol (175 mg) as a solid, m.p.156-157° C.; microanalysis, found: C, 82.5; H, 7.5; N, 4.5%; C₂₂ H₂₃ NO.0.1CH₃ CN requires: C, 82.9; H, 7.3; N, 4.79%; NMR( CD₃ !₂ SO):1.20-1.35(1H,m), 1.40-1.56(1H,m), 1.65-1.80(1H,m), 1.80-1.95(2H,m),2.05(CH₃ CN solvent), 2.50-2.70(4H,m), 2.75-2.85(1H,d), 2.94-3.04(1H,d),4.10(2H,s), 5.57(1H,s), 7.12-7.33(8H,m) and 7.35-7.43(1H,d); m/z 318(M+H).

The 2-benzyl-1-phenyltrifluoromethane sulphonate used as startingmaterial was prepared as follows.

Trifluoromethane sulphonic anhydride (6.5 ml) was added dropwise to astirred solution of 2-hydroxydiphenylmethane (6.45 g) in pyridine (50ml) at 0° C. under an atmosphere of argon. The reaction mixture wasstirred for 2.5 hours at 0° C. and then allowed to warm to +15° C. Thereaction mixture was poured into water and extracted with ethyl acetate.The ethyl acetate extract was washed with water, saturated brine, dried(MgSO₄) and evaporated. The residue was purified by flash columnchromatography on silica gel (Merck Art 9385) using 5% ethylacetate/hexane as eluent to give 2-benzyl-1-phenyltrifluoromethanesulphonate as an oil (9.1 g); microanalysis, found: C, 53.1; H, 3.6%;C₁₄ H₁₁ F₃ O₃ S requires: C, 53.2; H, 3.51%; NMR( CD₃ !₂ SO): 4.05(2H,s)and 7.14-7.49(9H,m); m/z 316(M).

EXAMPLE 20

A solution of sodium hydroxide (8.5 g) in water (90 ml) was added atambient temperature to a stirred mixture of quinuclidin-3-one (8.9 g),2-hydroxydiphenylmethane (13.0 g) and trimethylsulphoxonium iodide (31.2g) in toluene (150 ml). The mixture was stirred at ambient temperaturefor 3 days under an atmosphere of argon.

The mixture was filtered through diatomaceous earth and the filtercakewas washed with ethyl acetate (3×60 ml). The filtrate and washings werecombined and the organic layer was separated and retained. The aqueouslayer was extracted with ethyl acetate (4×130 ml). The retained organiclayer and the ethyl acetate extracts were combined and extracted with 2Maqueous hydrochloric acid (4×25 ml). The acid extracts were combined,washed with ethyl acetate (2×100 ml), cooled in ice, basified with 40%sodium hydroxide solution (30 ml) and extracted with ethyl acetate (4×70ml). The ethyl acetate extracts were combined, washed with saturatedbrine (50 ml), dried (Na₂ SO₄) and evaporated. The residue was purifiedby column chromatography on silica gel (Merck 7736) to give (aftertrituration with n-pentane) 3-(2-benzylphenoxymethyl)quinuclidin-3-ol(0.13 g) as a colourless solid, m.p. 71-73° C.; microanalysis, found: C,77.1; H, 7.8; N, 4.5%; C₂₁ H₂₅ NO₂ 0.2H₂ O requires: C, 77.1; H, 7.8; N,4.3%; NMR(CDCl₃): 1.2-1.4(1H,m), 1.4-1.6(2H,m), 1.65-2.1(3H,m),2.5-3.0(6H,m), 3.65-3.8(1H,d), 3.9-4.1(3H,m), 6.8-6.9(1H,d),6.9-7.0(1H,m) and 7.05-7.35(7H,m); m/z 324(M+H).

EXAMPLE 21

An ice-cooled solution of 3M aqueous hydrochloric acid (9 ml) in acetone(27 ml) was added to3-(2-benzyl-4-propionamidophenoxymethyl)-3-hydroxyquinuclidine boranecomplex (1.9 g). The latter dissolved immediately and the resultingcolourless solution was stirred at 5° C. for 1.5 hours. The reactionmixture was evaporated and the residue was dissolved in 2M aqueoushydrochloric acid (50 ml). This acidic aqueous solution was washed withethyl acetate (3×25 ml), basified with solid sodium carbonate, andextracted with ethyl acetate (3×70 ml). The ethyl acetate extracts werecombined, dried (Na₂ SO₄), and evaporated. The residue was dissolved inhot ethyl acetate (10 ml) and the resulting solution was added to a hotsolution of fumaric acid (0.46 g) in ethyl acetate (40 ml)/ethanol (10ml). The cooled mixture was evaporated to give a foam. This wastriturated with ethyl acetate/ether to give a solid which was storedunder vacuum over phosphorus pentoxide for 18 hours. There was thusobtained 3-(2-benzyl-4-propionamidophenoxymethyl)quinuclidin-3-olfumarate (1.2 g) as a solid, m.p. 70-85° C.; microanalysis, found: C,63.2; H, 7.1; N, 4.7%; C₂₄ H₃₀ N₂ O₃ fumarate, 1.0 H₂ O, 0.33 ethylacetate, 0.13 ether requires: C, 63.2; H, 7.1; N,4.9%; NMR ( CD₃ !₂ SO):1.0-1.1(3H,t), 1.4-1.8(3H,m), 2.0-2.3(4H,m), 2.8-3.2(6H,m),3.9-4.1(4H,m), 4.5-6.5(1H+H₂ O), 6.45-6.55(2H,s), 6.85-7.0 (1H,d)7.1-7.35(6H,m), 7.4-7.5(1H,m), 9.6-9.7(1H,s); m/z 395 (M+H).

The 3-(² -benzyl-4-propionamidophenoxymethyl)-3-hydroxyquinuclidineborane complex used as starting material was obtained as follows.

A solution of borane-tetrahydrofuran complex (135 ml of a 1M solution intetrahydrofuran) was added portionwise over a period of 30 minutes to astirred solution of 3-quinuclidinone (16.9 g) in dry tetrahydrofuran(300 ml) at -70° C. The mixture was stirred at -70° C. for 30 minutes.Water (20 ml) was added to the reaction mixture at -70° C. The solventwas removed by evaporation. A saturated solution of brine (250 ml) wasadded to the residue and the mixture basified by addition of solidsodium carbonate. The mixture was extracted with dichloromethane (4×100ml). The dichloromethane extracts were combined, silica gel (Merck 9385,60 g) added and the mixture evaporated to give a free flowing powder.This pre-absorbed material on silica gel was purified by flash columnchromatography on a further portion of silica gel using a mixture of 25%ethyl acetate/pentane as eluent to give 3-quinuclidinone borane complex(17.0 g) as a colourless solid, m.p. 162-164° C.; NMR (CDCl₃):0.7-2.3(3H, br), 2.0-2.3(4H, m), 2.7(1H, m), 3.0-3.4(4H, m) and 3.5(2H,s).

Powdered trimethyl sulphoxonium iodide (24.4 g) was added portionwise toa stirred, ice-cooled, suspension of sodium hydride (60% w/w dispersionin mineral oil, 4.4 g; the oil was removed by washing the solid withpetroleum ether) in dry dimethyl formamide (140 ml) under an atmosphereof argon whilst maintaining the temperature at 10 to 15° C. The mixturewas allowed to warm to room temperature. Solid 3-quinuclidinone boranecomplex (15.5 g) was added to the stirred mixture whilst maintaining thetemperature at 25-30° C. using an ice-bath. The mixture was then stirredat room temperature for 16 hours.

The mixture was poured into water (1400 ml) and the mixture wasextracted with ethyl acetate (4×400 ml).

The ethyl acetate extracts were combined, washed with water (3×300 ml),dried (Na₂ SO₄) and evaporated. The residue was purified by flash columnchromatography on silica gel using dichloromethane as eluent to give3-methylenequinuclidine oxide borane complex (13.8 g) as a colourlesssolid, m.p. 74-77° C.; microanalysis, found: C, 63.1; H, 10.6; N, 9.2%;C₈ H₁₆ BNO requires: C, 62.8; H, 10.5; N, 9.2%; NMR (CDCl₃): 0.6-2.3(3H,br), 1.6(1H, m), 1.7-1.9(1H, m), 1.9-2.0(2H, m), 2.1-2.3(1H, m), 2.8(2H,q) and 2.9-3.4(6H, m); m/z 152 (M-H).

Solid potassium carbonate (1.6 g) was added to a solution of2-benzyl-4-propionamidophenol (1.5 g) and 3-methylene quinuclidine oxideborane complex (0.9 g), in dry dimethylformamide (10 ml) under anatmosphere of argon. The mixture was stirred for 3 hours at 70° C. Themixture was poured into water (100 ml) and the mixture was extractedwith ethyl acetate (3×70 ml). The ethyl acetate extracts were combined,washed with 2M aqueous sodium hydroxide solution (2×25 ml) and water(2×25 ml), dried (Na₂ SO₄) and evaporated to give a gum (2.6 g). Thisgum was purified by flash column chromatography on silica gel (Merck ArtNo 9385) using 20% ethyl acetate/dichloromethane as eluent. There wasthus obtained3-(2-benzyl-4-propionamidophenoxymethyl)-3-hydroxyquinuclidine boranecomplex as a gum (2.0 g); NMR(CDCl₃): 0.5-2.5(3H, v.br), 1.2-1.3(3H,t),1.4-1.75(3H,m), 1.9-2.25(3H,m), 2.3-2.5(2H,q), 2.7-3.2(6H,m),3.7-3.9(2H,q), 3.9-4.0(2H,s), 6.7-6.8(1H,d), 7.05-7.5(8H,m); m/z 407(M-H).

The 2-benzyl-4-propionamidophenol used as starting material was preparedas follows.

Sodium nitrite (9.48 g) was added to a solution of sulphanilic acid(24.9 g) and sodium carbonate (6.78 g) whilst maintaining thetemperature of the reaction mixture at 5° C. The resulting mixture wascarefully poured into a mixture of concentrated hydrochloric acid (27 mlof a 28% solution) and ice (150 g). The mixture was allowed to stand forhalf an hour and the mixture was then added to a mixture of2-benzylphenol (24 g), 4.7M aqueous sodium hydroxide (150 ml) and ice(150 g) whilst maintianing the temperature below 5° C. The mixture wasstirred for one hour, sodium dithionite (58.8 g) was added and themixture slowly heated to 70° C. The reaction mixture was then allowed tocool to ambient temperature to give a precipitate which was collected byfiltration to give a solid (23.47 g). To a solution of this solid (20 g)in water (150 ml), propionic anhydride (32.5 g) was added and theresulting solution heated on a steam bath for 2.5 hours. The solutionwas allowed to cool to ambient temperature and to stand overnight. Themixture was then extracted with ethyl acetate (100 ml). The ethylacetate extract was washed with 2N aqueous hydrochloric acid (2×100 ml),saturated aqueous sodium hydrogen carbonate solution (3×100 ml) andwater (100 ml), dried (MgSO₄) and evaporated to give a2-benzyl-4-propionamidophenol as a tarry oil (120.72 g); NMR CD₃ OD!:1.15(3H,t), 2.30(2H,q), 3.9(2H,s), 6.75(1H,d) and 7.05-7.3(7H,m).

EXAMPLES 22-64

Using a similar procedure to that described in Example 1 (withexceptions as noted) the following compounds of formula 1 (in which Aand B are as indicated below) were prepared from the correspondingcompounds of formula 2 (in which Z is bromo unless indicated otherwise)and 3-ethynyl-3-hydroxyquinuclidine. Where compounds of formula 2 arenot commercially available preparative details are given.

EXAMPLE 22 A=H, B=CH₂ CH₂ CO₂ Et

Purified by flash column chromatography on silica gel using 10% methanolin dichloromethane as eluent, followed by recrystallisation from ethylacetate to give the title compound as a solid, m.p. 142.2° C.; NMR:1.5(3H,t), 1.30(1H,m), 1.59(1H,m), 1.88(2H,m), 2.62(2H,t), 2.72(4H,m),2.82(2H,t), 3.05(1H,m), 3.31(1H,s), 4.03(2H,q), 5.51(1H,s), 7.20(2H,d)and 7.29(2H,d).

The compound of formula 2 (Z=trifluoromethylsulphonyloxy), m/z 328(M+H),used as starting material was prepared using an analogous procedure tothat described in Example 1 for the preparation of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate from ethyl 3-(3-allyl-4-hydroxy)phenyl!propionate.

EXAMPLE 23 A=allyl, B=CH₂ CH₂ CO₂ Me

Purified by flash chromatography on silica gel using 10% methanol indichloromethane as eluent, to give the title compound as a solid, m.p.63-65° C., NMR(CDCl₃): 1.44(1H,), 1.68(1H,m), 2.10(4H,m), 2.62(2H,t),2.86(6H,m), 3.08(1H,d), 3.32(1H,d), 3.50(2H,d), 3.68(3H,s), 5.05(2H,m),5.96(1H,m), 7.00(2H,m) and 7.33(1H,d).

The compound of formula 2 (Z=trifluoromethylsulphonyloxy), m/z 354(M+H),used as starting material was prepared using an analogous procedure tothat described in Example 1 for the preparation of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate from ethyl 3-(3-allyl-4-hydroxy)phenyl!propionate.

EXAMPLE 24 A=H, B=CH═CHCO₂ Et

Purified by crystallisation from ethyl acetate to give the titlecompound as a solid, m.p. 180.7° C., NMR: 1.27(3H,t), 1.38(1H,m),1.65(1H,m), 1.93(3H,m), 3.05(7H,m), 4.20(2H,q), 5.62(1H,s), 6.63(1H,d),7.42(2H,d), 7.63(1H,d) and 7.70(1H,d).

The compound of formula 2 (Z=trifluoromethylsulphonyloxy), m/z 326(M+H),used as starting material was prepared using an analogous procedure tothat described in Example 1 for the preparation of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate from ethyl 3-(3-allyl-4-hydroxy)phenyl!propionate.

EXAMPLE 25 A=allyl, B=CH═CHCO₂ Et

Purified by chromatography on alumina (Fluka 507C) using a 19:1 (v/v)mixture of ethyl acetate/methanol as eluent, followed by triturationwith diethyl ether to give the title compound as a solid, m.p. 141.4°C.; NMR: 1.30(4H,m), 1.60(1H,m), 1.90(3H,m), 2.98(6H,m), 3.52(2H,d),4.20(2H,q), 5.07(2H,m), 5.61(1H,s), 5.90(1H,m), 6.60(1H,d), 7.39(1H,d)and 7.60(3H,m).

The compound of formula 2 (Z=trifluoromethylsulphonyloxy), m/z 366(M+H),used as starting material was prepared using an analogous procedure tothat described in Example 1 for the preparation of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate from ethyl 3-(3-allyl-4-hydroxy)phenyl!propionate.

EXAMPLE 26 A=allyl, B=(CH₂)₃ CO₂ Me

Obtained as a solid, m.p. 34-35° C., NMR(CDCl₃): 1.43(1H,m), 1.65(1H,m),2.01(4H,m), 2.30(2H,t), 2.61(2H,t), 2.85(4H,m), 3.05(1H,d), 3.32(1H,d),3.67(3H,s), 5.04(2H,m), 5.97(1H,m), 6.97(2H,m) and 7.31(1H,m).

The compound of formula 2(Z=trifluoromethylsulphonyloxy), m/z 368(M+H),used as starting material was prepared from the methyl ester of4-(4-hydroxyphenyl)butanoic acid using a method analogous to thatdescribed in Example 1 for the preparation of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate.

EXAMPLE 27 A=allyl, B=(CH₂)₄ CO₂ Me

Purified by chromatography on alumina (Fluka 507C) using a 19:1 (v/v)mixture of ethyl acetate/methanol as eluent to give the title compoundas a solid, m.p. 35-37° C.; NMR(CDCl₃): 1.44(1H,m), 1.70(5H,m),2.02(3H,m), 2.31(2H,t), 2.60(2H,t), 2.86(4H,m), 3.05(1H,d), 3.33(1H,dd),3.50(2H,d), 3.67(3H,s), 5.03(2H,m), 5.95(1H,m), 6.97(2H,m) and7.31(1H,d).

The compound of formula 2 (Z=trifluoromethylsulphonyloxy), m/z 382(M+H),was prepared from methyl 5-(4-hydroxyphenyl)pentanoate using a methodanalogous to that described in Example 1 for the preparation of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate.

EXAMPLE 28 A=allyl, B=CH₂ CH₂ CO₂ CH(Me)Et

Purified by flash chromatography on silica gel using a 9:1 (v/v) mixtureof dichloromethane/methanol as eluent to give a solid, m.p. 49-51° C.;NMR(CDCl₃): 0.86(3H,t), 1.15(3H,d), 1.55(4H,m), 2.05(3H,m), 2.58(2H,t),2.86(6H,m), 3.06(1H,d), 3.34(1H,d), 3.51(2H,d), 3.82(1H,m), 5.05(2H,m),5.97(1H,m), 7.01(2H,m) and 7.32(1H,d).

The compound of formula 2(Z=trifluoromethylsulphonyloxy), (M+H)=396,used as starting material was prepared by using a method analogous tothat described in Example 1 for the preparation of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate.

EXAMPLE 29 A=allyl, B=(CH₂)₂ CO₂ CH₂ CO₂ Me

Purified by chromatography on alumina (Fluka 50C) using a 19:1 (v/v)mixture of ethyl acetate/methanol as eluent to give a solid, m.p. 73-75°C.; NMR(CDCl₃): 1.42(1H,m), 1.67(1H,m), 2.01(3H,m), 2.33(1H,m),3.03(1H,d), 3.32(1H,dd), 3.50(2H,d), 3.75(3H,s), 4.61(2H,s), 5.04(2H,d),5.95(1H,m), 7.02(2H,m) and 7.33(1H,d).

EXAMPLE 30 A=allyl, B=(C₂)₂ CO₂ (CH₂)₂ OM

Purified by chromatography on alumina (Fluka 507C) using a 19:1 (v/v)mixture of ethyl acetate/methanol as eluent to give an oil, NMR(CDCl₃):1.44(1H,m), 1.69(1H,m), 2.06(3H,m), 2.62(2H,t), 2.87(6H,m), 3.10(1H,m),3.35(4H,m), 3.52(4H,m), 4.21(2H,m), 5.04(2H,m), 5.95(1H,m), 7.02(2H,m)and 7.32(1H,d).

EXAMPLE 31 A=H, B=OCH₂ CH₂ OCH₂

Purified by flash chromatography on silica gel using 10% methanol indichloromethane containing 1% ammonia (density, 0.88 g/cm³) as eluent togive a gum, NMR( CD₃ !₂ SO): 1.5-1.7(3H,m), 1.9-2.1(2H,m),2.8-3.65(6H,m), 3.3(3H,s), 3.3-3.4(1H,m), 3.6-3.68(2H,m),4.05-4.13(2H,m), 6.9(2H,d) and 7.32(2H,d).

EXAMPLE 32 A=allyl, B=CO₂ CH₂ CH₂ OCH₃

Purified by flash chromatography on silica gel using 10% methahol indichloromethane containing 1% ammonia (density, 0.88 g/cm³) as eluent togive a solid, m.p. 90-92° C., NMR: 1.21-1.41(1H,m), 1.50-1.69(1H,m),1.75-2.02(3H,m), 2.68(4H,t), 2.80-3.15(2H,q), 3.30(3H,s),3.53-3.70(4H,m), 4.35-4.45(2H,m), 5.00-5.16(2H,m), 5.67(1H,s),5.87-6.10(1H,m), 7.50-7.57(1H,d) and 7.77-7.85(2H,m).

The compound of formula 2 (Z=trifluoromethylsulphonyloxy) used asstarting material was prepared as follows.

Anhydrous potassium carbonate (55 g) in acetone (400 ml) and allylbromide (41.5 ml) were added to a stirred solution of methyl4-hydroxybenzoate (60.8 g). The mixture was heated at reflux for 18hours. The reaction mixture was cooled to ambient temperature, filteredand the residue washed with ethyl acetate. The filtrates and washingswere combined, evaporated and the residue dissolved in dichloromethane.The organic phase was washed with 1M aqueous sodium hydroxide (2×75 ml),water, brine and dried (MgSO₄). Evaporation gave methyl4-allyloxybenzoate as an oil (76.4 g) which was used without furtherpurification.

A mixture of methyl 4-allyloxybenzoate (1.92 g), sodium cyanide (50 mg)and 2-methoxyethanol (20 ml) was heated at reflux for 24 hours. Themixture was evaporated to give an oil which was partitioned betweendichloromethane and water. The organic phase was separated, washed withbrine, dried (MgSO₄) and evaporated. The residue was purified by flashcolumn chromatography on silica gel using a 9:1 (v/v) mixture ofpentane/ethyl acetate as eluent to give 2-methoxyethyl4-allyloxybenzoate (1.7 g) as an oil; NMR(CDCl₃): 3.44(3H,s),3.72(2H,t), 4.44(2H,t), 4.55-4.64(2H,m), 5.27-5.48(2H,m),5.96-6.14(1H,m), 6.93(2H,d) and 8.01(2H,d); m/z237(M+H).

2-methoxyethyl 4-allyloxybenzoate (1.7 g) was heated at 250-260° C. for0.5 hour and the crude product was purified by flash columnchromatography on silica gel using 3:2 (v/v) mixture of pentane/ethylacetate as eluent to give 2-methoxyethyl 3-allyl-4-hydroxybenzoate as anoil (1.36 g); NMR(CDCl₃): 3.42(2H,d), 3.44(3H,s), 3.74(2H,t),4.44(2H,q), 5.08-5.20(2H,m), 5.89-6.10(1H,m), 6.02(1H,s), 6.81(1H,d) and7.77-7.85(2H,m); m/z237(M+H).

The triflate was prepared using trifluoromethane sulphonic anhydrideusing the procedure described in Example 1 for the preparation of3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate. There wasthus obtained 2-allyl-4-methoxyethoxycarbonylphenyltrifluoromethanesulphonate as an oil; NMR(CDCl₃): 3.42(3H,s), 3.47-3.57(2H,d),3.72(2H,t), 4.48(2H,t), 5.07-5.25(2H,m), 5.80-6.05(1H,m),7.30-7.40(1H,d) and 7.95-8.08(2H,m); m/z 369(M+H).

EXAMPLE 33 A=H, B=OCH₂ CH₂ SCH₃

Purified by triturating with diethyl ether, followed byrecrystallisation from acetonitrile to give a solid, m.p. 154-155° C.,NMR: 1.2-1.4(1H,m), 1.5-1.6(1H,m), 1.8-2.0(3H,m), 2.15(3H,s),2.68(4H,t), 2.7-2.9(3H,m), 3.05(1H,d), 4.17(2H,t), 6.92(2H,d) and7.32(2H,d).

The compound of formula 2 (Z=bromo) was prepared as follows.

Diethyl azodicarboxylate (13.4 g) was added over a period of 20 minutesto a stirred solution of 4-bromophenol (12 g), 2-methylthioethanol (6.4g) and triphenylphospine (18.2 g) in tetrahydrofuran (250 ml) at -5° C.under an atmosphere of argon. The mixture was stirred at ambienttemperature for 1 hour and the solvent was then removed by evaporation.The residue was partitioned between dichloromethane (150 ml) and water(150 ml). The aqueous phase was separated and extracted withdichloromethane (150 ml). The dichloromethane extracts were combined,washed with water (2×100 ml), dried (MgSO₄) and evaporated. The residuewas dissolved in a boiling mixture of toluene (50 ml) and n-heptane (50ml). The solution was chilled and the precipitated triphenylphosphineoxide removed by filtration. The filtrate was evaporated and purified bymedium pressure chromatography on silica gel using a 1:1 (v/v) mixtureof toluene/n-heptane as eluent to give1-(4-bromophenoxy)-2-methylthioethane as an oil (10.2 g); NMR(CDCl₃):2.2(3H,s), 2.88(2H,t), 4.12(2H,t), 6.77(2H,d) and 7.37(2H,d).

EXAMPLE 34 A=H, B=CH₂ OCH₂ OCH₃

Purified by triturating with diethyl ether, followed byrecrystallisation from acetonitrile, to give a solid, m.p. 148-150° C.;NMR: 1.2-1.4(1H,m), 1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.6-2.75(4H,t),2.75-2.9(1H,d), 3.0-3.1(1H,d), 3.3(3H,s), 4.5(2H,s), 4.65(2H,s),5.5(1H,s) and 7.23-7.45(4H,dd).

The compound of formula 2 (Z=bromo) was prepared as follows.

Dimethoxymethane (80 ml) and phosphorous pentoxide (40 g) were added toa solution of 4-bromobenzyl alcohol (3.74 g) in dry dichloromethane (80ml). The resultant slurry was stirred for one hour at room temperatureand was then added to a cooled saturated sodium carbonate solution (600ml). The mixture was extracted with ether (3×200 ml). The organicextracts were combined, washed with water (25 ml), brine (25 ml), driedwith (MgSO₄) and evaporated.

The residue was purified by vacuum flash chromatography on silica gel(Merck 7736) using 50% toluene/hexane as eluent to give4-bromobenzyloxymethoxymethane as a colourless oil 2.6 g. NMR: (CDCl₃):3.4(3H,s), 4.5(2H,s), 4.7(2H,s), 7.2-7.3(2H,d) and 7.4-7.5(2H,d).

EXAMPLE 35 A=allyl, B=(CH₂)₃ OCH₃

Purified by flash chromatography on silica gel using 5% methanol indichloromethane containing 0.5% ammonia (density, 0.88 g/cm³) as eluentto give an oil, NMR: 1.3-1.5(1H,m), 1.55-1.7(1H,m), 1.7-1.85(2H,m),1.85-2.05(3H,m), 2.55-2.65(2H,t), 2.7-2.9(4H,m), 2.9-3.0(1H,d),3.1-3.2(1H,d), 3.2(3H,s), 3.25-3.35(2H,t), 3.45-3.5(2H,d),5.0-5.1(2H,m), 5.7(1H,s), 5.9-6.1(1H,m), 7.0-7.1(2H,d) and7.2-7.3(1H,d).

The compound of formula 2 (Z=trifluoromethylsulphonyloxy) used asstarting material was prepared as follows.

Powdered potassium carbonate (4.14 g) and allyl bromide (3.99 g) wereadded to a stirred solution of 3-(4-hydroxyphenyl)propanol (4.56 g) inacetone (15 ml) under an atmosphere of argon. The mixture heated atreflux for 20 hours. After cooling to ambient temperature the solidpotassium bromide was removed by filtration and washed with ether. Thefiltrate and washings were combined, washed with 2M aqueous sodiumhydroxide (2×20 ml), water (1×20 ml), brine (20 ml), dried (MgSO₄) andevaporated. The residue was purified by vacuum flash chromatography onsilica gel (Merck 7736) using toluene as eluent to give3-(4-allyloxyphenyl) propanol as a colourless oil (4.6 g). NMR(CDCl₃):1.3(1H,s), 1.8-2.0(2H,m), 2.6-2.7(2H,t), 3.6-3.7(2H,t), 4.45-4.55(2H,m),5.2-5.5(2H,m), 5.95-6.15(1H,m), 6.8-6.9(2H,d) and 7.05-7.15(2H,d).

Thionyl chloride (2 ml) was added dropwise to a solution of3-(4-allyloxyphenyl)propanol (4.7 g) in toluene (50 ml) containingpyridine (2.5 ml). The reaction mixture was stirred for 16 hours at roomtemperature and was then added to water (80 ml). The mixture wasextracted with toluene (3×50 ml), washed with water (20 ml), brine (20ml) dried (MgSO₄) and evaporated.

The residue was purified by vacuum flash chromatography on silica gel(Merck 7736) using toluene as eluent to give, 3-(4-allyloxyphenyl)propylchloride (5.1 g); NMR(CDCl₃): 1.9-2.1(2H,m), 2.6-2.7(2H,t),3.85-4.1(2H,m), 4.45-4.55(2H,m), 5.2-5.5(2H,m), 5.9-6.2(1H,m),6.8-6.9(2H,d) and 7.0-7.1(2H,d).

A mixture of 3-(4-allyoxyphenyl)propyl chloride (6.1 g), dimethylformamide (50 ml), dibromomethane (25 ml) and sodium bromide (3.28 g)was heated for 16 hours at 100° C. The mixture was poured into water (20ml) and extracted with ether (3×50 ml). The organic extracts werecombined, washed with water (20 ml), brine (20 ml), dried (MgSO₄) andevaporated. The residue was purified by vacuum flash chromatography onsilica gel (Merck 7736) using 5% ethyl acetate in hexane as eluent togive 3-(4-allyloxyphenyl)propyl bromide as a colourless oil (4.0 g);NMR(CDCl₃): 2.0-2.2(2H,m), 2.65-2.8(2H,t), 3.3-3.4(2H,t),4.45-4.55(2H,m), 5.2-5.5(2H,m), 5.9-6.2(1H,m), 6.8-6.9(2H,d) and7.1-7.2(2H,d).

3-(4-allyoxyphenyl)propyl bromide (4.0 g) was added dropwise to a cooledsolution of methanol (50 ml) and mercury II perchlorate prepared frommercury II oxide (3.39 g) and 60% perchloric acid (4.71 ml). The mixturewas stirred for 16 hours at room temperature. Saturated brine (80 ml)was added and the mercury salts were removed by filtration and theresidue washed with ether (30 ml). The aqueous layer from the filtratewas separated and further extracted with ether (3×100 ml). The organicextracts were combined, were washed with water (2×20 ml), brine (1×20ml), dried (MgSO₄) and evaporated.

The residue was purified by flash chromatography on silica gel using 5%ethyl acetate in toluene as eluent to give3-(4-allyloxyphenyl-1-methoxypropane as a colourless oil (1.6 g)NMR(CDCl₃): 1.8-2.0(2H,m), 2.6-2.7(2H,t), 3.3-3.5(5H,m),4.45-4.55(2H,m), 5.2-5.5(2H,m), 5.95-6.15(1H,m), 6.8-6.9(2H,d) and7.05-7.15(2H,d).

The 3-(4-allyloxyphenyl)-1 methoxypropane was heated at 200° C. for 2hours under an atmosphere of argon. The product was dissolved in etherand extracted with 2M aqueous sodium hydroxide (4×20 ml). The aqueousextracts were combined, and acidified with 2M aqueous hydrochloric acid.The mixture was extracted with ether (2×30 ml), the ether extracts werecombined, washed with water (10 ml), brine (10 ml), dried (MgSO₄) andevaporated to give 3-(2-allyl, 4-hydroxyphenyl), 1-methoxypropane acolourless oil (940 mg) which was used without further purification;NMR(CDCl₃): 1.8-2.0(2H,m), 2.5-2.6(2H,t), 3.3-3.45(7H,t), 4.8(1H,s),5.1-5.2(2H,m), 5.9-6.1(1H,m), 6.7-6.8(1H,d) and 6.9-7.0(2H,d).

Using a similar procedure to that described in Example 1 for thepreparation of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate but using3-(2-allyl-4-hydroxyphenyl)-1-methoxypropane as starting material therewas obtained 2-allyl-4-(3-methoxypropyl)phenyl trifluoromethanesulphonate as a colourless oil; NMR(CDCl₃): 1.8-1.95(2H,m),2.65-2.75(2H,t), 3.3-3.5(7H,m), 5.05-5.2(2H,m), 5.8-6.0(1H,m) and7.0-7.3(3H,m).

EXAMPLE 36 A=H, B=CH₂ CH₂ OCH₂ CH₂ OCH₃

Purified by flash chromatography on silica gel using 5% methnol indichloromethane containing 0.5% ammonia (density, 0.88 g/cm³) as eluantto give a solid, m.p. 126-127° C.; NMR: 1.2-1.4(1H,m), 1.5-1.65(1H,m),1.8-2.0(3H,m), 2.6-2.7(4H,t), 2.75-2.9(3H,m), 3.0-3.1(1H,d), 3.25(3H,s),3.35-3.45(2H,m), 3.45-3.55(2H,m), 3.55-3.65(2H,t), 5.55(1H,s),7.2-7.3(2H,d) and 7.3-7.4(2H,d).

The compound of formula 2 (Z=bromo) used as starting material wasprepared as follows.

4-bromophenethyl bromide (4.0 g) was added in a dropwise manner to acooled solution of methoxyethanol (50 ml) and mercury II perchlorate(prepared from 3.39 g of mercury II oxide and 4.71 g of 60% perchloricacid). The mixture was stirred overnight at ambient temperature.Saturated brine (80 ml) was added, the mercury salts removed byfiltration and washed with ether. The filtrate was extracted with ether(3×100 ml). The ether extracts were combined, washed with water (20 ml),saturated brine (20 ml), dried (MgSO₄) and evaporated. The residue waspurified by flash chromatography on silica gel using 10% ethyl acetatein toluene as eluent to give 1-(-4-bromophenethyloxy)-2-methoxyethane(2.2 g) as a colourless oil; NMR(CDCl₃): 2.8-2.9(2H,t), 3.4(3H,s),3.5-3.6(4H,m), 3.6-3.75(2H,t 7.05-7.15(2H,d) and 7.35-7.45(2H,d).

EXAMPLE 37 A=H, B=CONHCH₂ CO₂ Me

Purified by flash chromatography on silica gel using 10% methanol indichloromethane containing 1% ammonia (density 0.88 g/cm³) as eluent,followed by recrystallisation from ethanol to give a solid, m.p.200-202° C.; NMR: 1.2-1.4(1H,m), 1.5-1.7(1H,m), 1.8-2.0(3H,m),2.6-2.8(4H,m), 2.8-2.9(1H,d), 3.05-3.15(1H,d), 5.65(1H,s), 3.78(3H,s),4.15(2H,s), 6.0(1H,s), 7.6(2H,d), 8.0(2H,d) and 9.12(1H,m).

The compound of formula 2 (Z=iodo) used as starting material wasprepared as follows:

Triethylamine (5.4 ml) was added to a solution of 4-iodobenzoyl chloride(5.06 g) in dichloromethane (30 ml) at 5° C. Glycine methyl esterhydrochloride (2.4 g) was then added to the reaction mixture and themixture was stirred at 5° C. for 2 hours. The mixture was then stirredat ambient temperature overnight. Dichloromethane (100 ml) was added andthe mixture was washed with water (2×100 ml), dried (MgSO₄) andevaported. The residue was triturated with pentane to give a solid whichwas collected by filtration to give methyl 4-iodohippurate, m.p.166-168° C. NMR: 3.65(3H,s), 4.0(2H,d), 7.65(2H,m), 7.88(2H,m) and9.0(1H,m); m/z 320(M+H).

EXAMPLE 38 A=H, B=CONH(CH₂)₂ OCH₃

Purified by flash chromatography on silica gel using 10% methanol indichloromethane containing 1% ammonia (density, 0.88 g/cm³) as eluentfollowed by recrystallisation acetonitrile to give a solid, m.p.165-167° C.; NMR: 1.2-1.4(1H,m), 1.5-1.7(1H,m), 1.8-2.0(3H,m),2.6-2.8(4H,m), 2.8-2.9(1H,d), 3.05-3.15(1H,d), 3.3(2H,m), 3.45(5H5.64(1H,s), 5.65(1H,s), 7.45(2H,d), 7.82(2H,d) and 8.5(1H,m).

The compound of formula 2 (Z=iodo) used as starting material wasprepared in an analogous manner to the compound of formula 2 in Example37 in 89% yield, NMR: 3.3(3H,s), 3.45(4H,m), 7.62(2H,m), 7.85(2H,m) and8.55(1H,m); m/z 306(M+H).

EXAMPLE 39 A=H, B=CH₂ OCOCH(CH₃)₂

Purified by flash chromatography on silica gel using a 80:20:3 (v/v/v)mixture of ethyl acetate/ethanol/triethylamine as eluent, followed bytrituration with acetonitrile to give a solid, NMR: 0.9(6H,d),1.2-1.4(1H,m), 1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.23(2H,d), 2.6-2.8(4H,m),2.8-2.9(1H,d), 3.05-3.15(1H,d), 5.1(2H 5.65(1H,s), 5.58(1H,s) and7.37(4H,m).

The compound of formula 2 (Z=bromo) was prepared as follows.

A mixture of 4-bromobenzyl alcohol (1 g) pyridine (0.6 ml) anddichloromethane (40 ml) was stirred under an atmosphere of argon at 3°C. for 0.5 hours. Isovaleryl chlorile (0.73 ml) was added to thereaction mixture dropwise over a period of 5 minutes. The mixture wasstirred at 5° C. for 15 minutes, allowed to warm to ambient roomtemperature and stirred at ambient temperature for 1 hour. The reactionmixture was washed with 2M aqueous hydrochloric acid (20 ml), water (20ml), and brine (20 ml), dried (MgSO₄) and evaporated to give acolourless oil (1.4 g). NMR: 0.9(6H,d), 2.0(2H,m), 2.2(2H,d),5.05(3H,m), 7.35(2H,m) and 7.6(2H,m); m/z 272 (M+H).

EXAMPLE 40 A=H, B=O(CH₂)₂ CN

Triturated with a 80:20:3 (v/v/v) mixture of ethylacetate/ethanol/triethylamine to give a solid, NMR: 1.2-1.4(1H,m),1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.6-2.8(4H,m), 2.8-2.9(1H,d),3.05-3.15(1H,d), 5.65(1H,s), 2.99(3H,t), 4.2(3H,t), 5.5(1H,s),6.95(2H,s) and 7.35(2H,s).

The compound of formula z (Z=iodo) used as starting material wasprepared as follows.

A 40% solution of benzyltrimethyl ammonium hydroxide in water (1.2 ml)was added to a stirred solution of 4-iodophenyl (4 g) in acrylonitrile(10 ml) whilst under an atmosphere of argon. The temperature of thereaction mixture was raised to 80° C., gradually over 2 hours and wasthen heated at reflux for 2 days. The reaction mixture was cooled toambient temperature, diluted with toluene (100 ml) and evaporated. Theresidue was partitioned between 1M aqueous sodium hydroxide (20 ml) andether (30 ml). The aqueous phase was separated and extracted with ether(2×30 ml). The ether extracts were combined, washed with water (20 ml),brine (20 ml), dried (MgSO₂) and evaporated to give a solid (1.6 g)which was used without further purification.

EXAMPLE 41 A=CHO, B=OCH₂ CH₂ OCH₃

Obtained as a solid, m.p. 116-118.5° C.; NMR(CDCl₃): 1.45(1H,m),1.70(1H,m), 2.05(3H,m), 2.84(4H,t), 3.09(1H,d), 3.3(1H,d), 3.45(3H,s),3.76(2H,m), 4.18(2H,m), 7.15(1H,dd), 7.48(2H,m) and 10.43(1H,s).

The compound of formula 2 (Z=trifluoromethylsulphonylloxy) used asstarting material was prepared as follows.

Bromoethylmethyl ether (105.7 g) was added to a stirred suspension ofhydroquinone monobenzylether and unhydrous potassium carbonate (84.5 g)in N,N-dimethylformamide (250 ml). The reaction mixture was heated at90° C. for 18 hours. The reaction mixture was allowed to cool to ambienttemperature and the mixture filtered. The filtrate was dissolved inwater (750 ml) and the aqueous mixture was extracted with ethyl acetate(5×150 ml). The ethyl acetate extracts were combined, washed with water(3×100 mls), brine (200 mls), dried (MgSO₄) and evaporated to give1-(benzyloxy)-4-(2-methoxyethoxy)benzene (102.4 g) as a solid; NMR:3.3(3H,s), 3.61(2H,m), 4.0(2H,m), 5.02(2H,s), 6.9(4H,m) and 7.4(5H,m)and m/z 259(M+H).

A mixture of 1-(benzyloxy)-4-(2-methoxyethoxy)benzene (180 g), ethanol(2000 ml) and palladium on carbon catalyst (20 g) was stirred under anatmosphere of hydrogen, at room temperature and atmospheric pressure.After the theoretical quantity of hydrogen had been consumed, thereaction mixture was filtered. The filtrate was evaporated to give asolid which was crystallised from a mixture of ethyl acetate andn-hexane to give 4-(2-methoxyethoxy)phenol as a solid (94.7 g) m.p.97.9° C.; microanalysis, found: C, 64.3%; H, 7.4%; C₉ H₁₂ O₃ requires:C, 64.3%; H, 7.2%; NMR: 3.35(3H,s), 3.6(2H,m), 3.95(2H,m), 6.7(4H,m) and8.9(1H,s); m/z 169(M+H).

A solution of 4-(2-methoxyethoxy)phenol in toluene (350 ml) was added toa solution of magnesium methoxide in methanol (8% by weight solution,331 mls), under an atmosphere of argon. The reaction mixture was heatedat reflux for 2 hours. Toluene (350 mls) was added and the reactionmixture distilled at atmospheric pressure until the internal temperaturereached 92° C. A mixture of paraformaldehyde in toluene (300 ml) wasadded to the reaction mixture and the reaction mixture was heated atreflux for 3.5 hours. The mixture was cooled to ambient temperature andthen stirred at ambient temperature for 18 hours. The reaction mixturewas diluted with toluene (400 ml), washed with 2M aqueous hydrochloricacid (2×150 ml) and water (to pH 1). The residue was distilled undervacuum to give 2-hydroxy-5-(2-methoxyethoxy)benzaldehyde as an oil (35g), bp 104-130° C. 0.01 mm Hg!; NMR(CDCl₃): 3.45(3H,s), 3.75(2H,m),4.12(2H,m), 6.92(1H,d), 7.05(1H,d), 7.2(1H,dd), 9.84(1H,s) and10.63(1H,s); m/z 197(M+H).

Trifluoromethyl sulphonic anhydride (3.88 ml) was added dropwise over aperiod of 10 minutes to a stirred solution of2-hydroxy-5-(2-methoxyethoxy)benzaldehyde (4.11 g) and2,6-dimethylpyridine (2.67 ml) in dichloromethane (20 ml) at 0° C. underan atmosphere of argon. After stirring at room temperature for 16 hours,the mixture was added to ice (100 g). The organic phase was separated,washed with 5% aqueous sodium carbonate solution (2×10 ml), dried(MgSO₄) and evaporated to give an oil which was purified by flash columnchromatography on silica gel using dichloromethane as eluent to give2-trifluoromethylsulphonyloxy-5-(2-methoxyethoxy)benzaldehyde (2.2 g) asan oil; NMR(CDCl₃): 3.45(3H,s), 3.78(2H,m), 4.19(2H,m), 7.3(2H,m),7.48(1H,d) and 10.23(1H,d); m/z 329(M+H).

EXAMPLE 42 A=allyl, B=OCH(CH₃)CO₂ CH₃

Purified by flash chromatography on silica gel using a 90:09:01 (v/v/v)mixture of ethyl acetate/methanol/ammonia (density, 0.88 g/cm³) aseluent to give an oil, NMR: (CDCl₃) 1.3-1.5(1H,m), 1.55-1.76(4H,m),1.9-2.5(3H,m), 2.7-3.0(4H,m), 3.0-3.2(1H,d), 3.2-3.4(1H,dd),3.4-3.5(2H,d), 3.7-3.8(3H,ms), 4.7-4.8(1H,d), 5.0-5.15(2H,m),5.8-6.05(1H,m), 6.6-6.8(2H,m) and 7.3-7.4(1H,d).

EXAMPLE 43 A=allyl, B=(CH₂)₂ CO₂ Me

Obtained as a gum, NMR: 1.2-1.5(5H,m), 1.5-1.9(3H,m), 1.9-2.15(4H,m),2.2-2.4(2H,t), 2.5-2.65(2H,t), 2.7-3.0(4H,m), 3.0-3.1(1H,d),3.3-3.4(1H,dd), 3.45-3.55(2H,d), 3.65(3H,s), 5.0-5.1(2H,m),5.9-6.1(1H,m), 6.9-7.0(2H,m) and 7.3-7.4(1H,d).

The compound of formula 2 (Z=trifluoromethylsulphonyloxy) used asstarting material was prepared in an analogous manner to the preparationof ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionatedescribed in Example 1.

EXAMPLE 44 A=allyl, B=(CH₂)₂ CO₂ (CH₂)₅ CH₃

Purified by chromatography on alumina (Fluka 507C) using a 19:1 (v/v)mixture of ethyl acetate/methanol as eluent to give a solid, m.p. 39-41°C., NMR(CDCl₃): 0.90(3H,t), 1.30(6H,s), 1.42(1H,m), 1.61(3H,m),2.00(3H,m), 2.26(2H,m), 2.58(2H,t), 2.86(6H,m), 3.05(1H,d), 3.30(1H,d),3.50(2H,d), 4.04(2H,t), 5.04(2H,m), 5.95(1H,m), 7.00(2H,m) and7.31(4H,d).

EXAMPLE 45 A=CH₂ CO₂ Et, B=H

Purified by crystallisation from acetonitrile to give a solid, m.p.137.5-138.5° C.; NMR: 1.2(3H, t), 1.3(1H, m), 1.6(1H, m), 1.8-2.0(3H,m), 2.7(4H, m), 2.8(1H, d), 3.1(1H, d), 3.8(2H, s), 4.1(2H, q), 5.6(1H,s) and 7.2-7.4(4H, m).

The compound of formula 2 (Z=iodo) used as starting material wasprepared as follows.

A solution of 2-(2-iodophenyl)acetonitrile (2.82 g) in a mixture of 1:1(v/v) ethanol/water (70 ml) was treated with sodium hydroxide (2.4 g)and stirred at reflux for 4 hours. The resultant solution was cooled toambient temperature, concentrated to 30 ml, diluted with water (100 ml)and washed with ethyl acetate (2×100 ml). The organic layers werecombined and extracted with 2M aqueous sodium hydroxide solution (100ml). The aqueous layer was acidified to pH 1 with concentratedhydrochloric acid and filtered. The solid collected was washed withwater and vacuum dried to give 2-(2-iodophenyl)acetic acid (1.45 g) as asolid, m.p. 110-113° C.; microanalysis; found: C, 36.9; H; 2.7%; C₈ H₇IO₂ requires: C, 36.7; H, 2.7%; NMR: 3.7(2H, s), 7.0(1H, m), 7.4(2H, m),7.8(2H, d); 12.5(1H, br s).

Extraction of the acidic aqueous layers with dichloromethane gave afurther portion of the same product (0.5 g), >90% pure by NMR.

A solution of 2-(2-iodophenyl)acetic acid in ethanol (20 ml) was treatedwith concentrated sulphuric acid (0.5 ml) and heated at reflux for 18hours. The resultant solution was cooled to ambient temperature,concentrated to 5 ml and diluted with saturated aqueous sodium hydrogencarbonate solution (30 ml). Extraction with ethyl acetate (2×50 ml) gavean oil (450 mg) which was purified by chromatography on silica geleluting with 20% ethyl acetate in hexane to give ethyl2-(2-iodophenyl)acetate as a solid, m.p. 40.5-41.5° C.; NMR: 1.2(3H, t),3.8(2H, s), 4.1(2H, q), 7.0(1H, m), 7.4(2H, m) and 7.9(1H, d).

EXAMPLE 46 A=CH₂ SEt, B=H

Purified by chromatography on silica gel (Varian Bond-Elut S1 silicagel) using a gradient of methanol in dichloromethane containing 1%ammonia (density, 0.88 g/cm³) as eluent, followed by crystallisationfrom acetonitrile, to give a solid, m.p. 126-127.5° C.; NMR: 1.2(3H, t),1.3(1H, m), 1.6(1H, m), 1.8-2.0(3H, m), 2.4(2H, q), 2.7(4H, m), 2.9(1H,d), 3.1(1H, d), 3.9(2H, s), 5.6(1H, s) and 7.2-7.4(4H, m).

The compound of formula 2 (Z=iodo) used as a starting material wasprepared using the procedures described for the preparation of thecompound of formula 2 in Example 47 except the reaction was carried outon double the scale and ethanethiol (0.65 ml) and potassium carbonate(1.32 g) were used in place of sodium methanethiolate.

There was thus obtained 2-ethylthiomethyliodobenzane (1.98 g) as acolourless oil; NMR: 1.2(3H, t), 2.4(2H, q), 3.8(2H, s), 7.0(1H, m),7.4(2H, m) and 7.9(1H, m).

EXAMPLE 47 A=CH₂ SMe, B=H

Purified by trituration with acetonitrile to give a solid, m.p.118-119.5° C., NMR: 1.2(1H, m), 1.4(1H, m), 1.7-1.8(3H, m), 1.8(3H, s),2.5(4H, m), 2.7(1H, d) 2.9(1H, d), 3.6(2H, s), 5.4(1H, s) and7.0-7.3(4H, m).

The starting material (Z=iodo) was prepared as follows.

A solution of 2-chloromethyliodobenzene (1.01 g) in ethanol (15 ml) wasdeoxygenated with a stream of argon and was then treated with sodiummethanethiolate (336 mg) and sodium borohydride (182 mg). The suspensionwas stirred vigorously at ambient temperature for 22 hours and was thendiluted with diethyl ether (40 ml), washed with water (2×30 ml) andbrine (30 ml). The aqueous layers were back-extracted with ether, theorganic layers were combined, dried (MgSO₄) and concentrated to give2-methylthiomethyliodobenzene (1.02 g) as a colourless oil (used in thenext step without further purification); NMR: 2.0(3H, s), 3.8(2H, s),7.0(1H, m), 7.4(2H, m)and 7.9(1H, d).

EXAMPLE 48 A=allyl, B=CO₂ (CH₂)₃ OCH₂ CH₃

Purified by flash chromatography on silica gel using 10% methanol indichloromethane containing 1% ammonia (density, 0.88 g/cm³) as eluent togive a solid, m.p. 75-77° C., NMR (CDCl₃): 1.20(3H,t), 1.34-1.53(1H, m),1.53-1.80(2H, m), 1.90-2.15(5H, m), 2.75-3.06(5H, m), 3.06(1H, d),3.32(1H, dd), 3.50(3H, q), 3.55(2H, t), 4.41(2H, t), 5.00-5.15(2H, m),5.88-6.05(1H, m), 7.45(1H, d) and 7.78-7.90(2H, m).

The compound of formula 2 (Z=trifluoromethylsulphonyloxy) was preparedfrom 3-ethoxypropyl-4-allyloxybenzoate using the method described inExample 1 for the preparation of3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate.

3-Ethoxypropyl-4-allyloxybenzoate was prepared as described in Example32 but using 3-ethoxy-1-propanol instead of 2-methoxyethanol. Theproduct was an oil; NMR (CDCl₃): 1.20(3H, t), 2.02(2H, quintet),3.43-3.62(4H, m), 4.38(2H, t), 4.55-4.64(2H, m), 5.27-5.49(2H, m),5.95-6.16(1H, m), 6.93(2H, d), 7.98(2H, d); m/Z 265 (M+H).

EXAMPLE 49 A=allyl, B=CH₂ CH₂ COCH₃

Purified by flash chromatography on silica gel using a 80:20:3 (v/v/v)mixture of ethyl acetate/ethanol/triethylamine as eluent followed bytrituration with diethyl ether to give a solid, 101-104° C., NMR:1.2-1.4 (1H, m), 1.5-1.7 (1H, m), 1.8-2.02 (3H, m), 2.1 (3H, s), 2.6-2.8(8H, m), 2.82-2.92 (1H, d), 3.05-3.15 (1H, d), 3.45 (2H, d), 5.05 (2H,m), 5.55 (1H, s), 5.9 (1H, m), 7.05 (2H, m) and 7.25 (2H, m).

The compound of formula 2 (Z=trifluoromethylsulphonyloxy) was preparedin a similar manner to the compound of formula 2 described in Example 1.Thus, the process described in Example 1 was used to convert4-(4-hydroxyphenyl)-2-butanone to 4-(4-allyloxyphenyl)-2-butanone whichwas obtained in 79% yield as an oil; NMR: 2.1 (3H, s), 2.7 (2H, m), 2.85(2H, m), 4.5 (2H, m), 5.25 (1H, m), 5.4 (1H, m), 6.0 (1H, m), 6.85 (2H,m) and 7.05 (2H, m).

In a similar manner to that described in Example 1,4-(4-hydroxyphenyl)-2-butanone was converted to4-(3-allyl-4-hydroxyphenyl)-2-butanone which was obtained as an oil;NMR: 2.05 (3H, s), 2.65 (4H, m), 3.25 (2H, d), 5.0 (2H, m), 5.9 (1H, m),6.65 (1H, d), 6.8 (2H, m) and 9.05 (1H, s).

In a similar manner to that described in Example 1,4-(4-hydroxyphenyl)-2-butanone was converted to4-(3-allyl-4-trifluoro-methylsulphonyloxyphenyl)-2-butanone in 80%yield, NMR: 2.15 (3H, s), 2.75 (2H, m), 2.9 (2H, m), 3.45 (2H, d), 5.1(2H, m), 5.9 (1H, m), 7.15 (3H, m). m/z 337 (M+H).

EXAMPLE 50 A=allyl, B=CO(CH₂)₂ CO₂ Et

Purified by flash chromatography on silica gel using a 80:20:3 (v/v/v)mixture of ethyl acetate/ethanol/triethylamine as eluent to give an oil,NMR: 1.18 (3H, t), 1.2-1.4 (1H, m), 1.5-1.7 (1H, m), 1.8-2.02 (3H, m),2.6-2.8 (4H, m), 2.82-2.92 (1H, d), 3.05-3.15 (1H, d), 3.22 (2H, m), 3.3(2H, m), 3.6 (2H, d), 4.15 (2H, q), 5.1 (2H, m), 5.75 (1H, s), 6.0 (1H,m), 7.5 (1H, d) and 7.8 (2H, d).

The compound of formula 2 (Z=trifluoromethylsulphonyloxy) used asstarting material was obtained as follows.

Sulphuric acid (98%, 1.0 ml) was added, dropwise, to a stirred solutionof 4-(4-hydroxyphenyl)-4-oxo-butyric acid (5.0 g), in ethanol (50 ml).The resulting solution was then heated at 50° C. for 18 hours. Thesolvent was evaporated and the residue was dissolved in ethyl acetate.The mixture was washed with saturated aqueous sodium bicarbonatesolution, water, dried (MgSO₄) and evaporated to give ethyl4-(4-hydroxyphenyl)-4-oxo butyrate as a solid (5.3 g), NMR: 1.15 (3H,t), 2.6 (2H, t), 3.2 (2H, t), 4.15 (2H, q), 6.85 (2H, m), 7.85 (2H, m)and 10.27 (1H, s).

Using a similar procedure to Example 1 but using ethyl4-(4-hydroxyphenyl)-4-oxobutyrate there was thus obtained ethyl4-(4-allyloxyphenyl)-4-oxobutyate (90% yield) as an oil; NMR CDCl₃ !:1.1 (3H, t), 2.65 (2H, t), 3.2 (2H, t), 4.15 (2H, q), 4.55 (2H, m), 5.3(2H, m), 6.0 (1H, m), 6.9 (2H, m) and 7.9 (2H, m).

Using a similar procedure as example 1 but using the above as startingmaterial there was thus obtained ethyl4-(3-allyl-4-hydroxy-phenyl)-4-oxobutyrate (25% yield) as a solid; NMR:1.18 (3H, t), 2.55 (2H, t), 3.15 (2H, t), 3.35 (2H, m), 4.15 (2H, q),5.05 (2H, m), 5.9 (1H, m), 6.9 (1H, m), 7.7 (2H, m) and 10.3 (1H, s).

Using a similar procedure as example 1 but using the above as startingmaterial there was obtained ethyl4-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)-4-oxobutyrate (85%yield) after purification (column chromatography on silica using 50%ethyl acetate/pentane as eluent) as an oil; NMR: 1.15 (3H, t), 2.65 (2H,t), 3.32 (2H, m), 3.55 (2H, m), 4.07 (2H, q), 5.18 (2H, m), 5.95 (1H,m), 7.58 (1H, m), 8.05 (2H, m).

EXAMPLE 51 A=allyl, B=COCH₂ CO₂ Et

Purified by flash chromatograph on silica gel using a 80:20:2 (v/v/v)mixture of ethyl acetate/ethanol/triethylamine as eluent to give an oil,NMR: 1.2 (3H, t), 1.2-1.4 (1H, m), 1.5-1.7 (1H, m), 1.8-2.02 (3H, m),2.6-2.8 (4H, m), 2.82-2.92 (1H, d), 3.05-3.15 (1H, d), 3.55 (2H, d),4.15 (4H, m), 5.1 (2H, m), 5.75 (1H, s), 6.0 (1H, m), 7.5 (1H, m) and7.75 (2H, m).

The compound of formula 2 (Z=trifluoromethylsulphonyloxy) used asstarting material was obtained as follows:

Diethyl carbonate (50 ml) was heated to reflux, under an atmosphere ofargon. The heat source was removed and freshly prepared sodium (3 g) wasadded over a period of 20 minutes. The reaction temperature was raisedto reflux and a hot solution of 3-allyl-4-hydroxyacetoxyphenone (7.8 g)in diethyl carbonate (80 ml) was added.

Ethanol produced (about 15 ml) during the reaction was removed at theelevated temperature of the reaction mixture together with some diethylcarbonate. Diethyl carbonate (150 ml) was then added to the reactionmixture and the reaction mixture heated at reflux for 2.5 hours.

The reaction mixture was cooled to 30° C. and ice water (50 ml) wasadded cautiously. The mixture was carefully neutralized by addition of3M aqueous hydrochloric acid (-40 ml) and the aqueous mixture wasextracted with diethyl ether (3×50 ml). The organic extracts werecombined, dried (MgSO₄) and evaporated to give an oil, which waspurified using dry flash chromatography on 60H silica (Merck Art. No.7736) using a mixture of ethyl acetate and toluene as eluent to giveethyl 4-(3-allyl-4-hydroxyphenyl)-3-oxo-propionate (7.2 g), NMR CDCl₃ !:1.2 (3H, t), 3.4 (2H, d), 3.95 (2H, s), 4.2 (2H, q), 5.1 (2H, m), 6.0(1H, m), 6.85 (1H, m) and 7.7 (2H, m); m/z=249 (M+H).

In an alternative procedure, triethylamine (0.28 ml) was added to an icecooled solution of ethyl 4-(3-allyl-4-hydroxyphenyl)-3-oxo-propionate(0.5 g), in dichloromethane (10 ml). The reaction mixture was stirredfor 5 minutes and trifluoromethane sulphonic anhydride (0.34 ml) wasthen added in a dropwise manner. The reaction mixture was stirred for 15minutes.

The reaction mixture was diluted with dichloromethane (20 ml), washedwith water (10 ml), brine (10 ml), dried (MgSO₄) and evaporated to givean oil which was purified by flash chromatography on silica gel usingtoluene as eluent, to give a colourless oil (0.7 g). m/z=381 (M+H).

EXAMPLE 52 A=H, B=CH₂ CH₂ CN

Purified by flash chromatography on silica gel using a 80:20:2 (v/v/v)mixture of ethyl acetate/ethanol/triethylamine as eluent to give a solid(0.13 g), NMR: 1.2-1.4 (1H, m), 1.5-1.7 (1H, m), 1.8-2.02 (3H, m),2.6-2.8 (4H, m), 2.75 (2H, m), 2.85 (2H, m), 2.82-2.92 (1H, d),3.05-3.15 (1H, d), 7.25 (2H, d) and 7.33 (2H, m).

The compound of formula 2 (Z=trifluoromethylsulphonyloxy) used asstarting material was prepared as follows:

Using a similar procedure to Example 1, but using3-(4-hydroxyphenyl)propionitrile (0.8 g), as the starting material, wasthus obtained 3-(4-trifluoromethylsulphonyloxyphenyl)propionitrile (1g); NMR: 2.85 (2H, m), 2.95 (2H, m), 7.5 (4, m); m/z=297 (M+NH₄).

EXAMPLE 53 A=CH₂ CO₂ CH₂ CH₂ CH₃, B=H

Obtained as a gum, NMR: 0.9(3H, t), 1.4(1H, m), 1.5-1.7(3H, m),1.8-2.0(3H, m), 2.7(4H, m), 2.9(1H, d), 3.1(1H, d), 3.8(2H, s), 4.0(2H,t), 5.7(1H, s), 7.2-7.4(4H, m).

The starting material of formula 2 (Z=iodo) was prepared in a similarmanner to the compound of formula 2 described in Example 54 exceptpropan-1-ol (0.16 ml) was substituted for propan-2-ol. There was thusobtained propyl 2-(2-iodophenyl)acetate (232 mg) as a yellow oil; NMR:0.9(3H, t), 1.6(2H, m), 3.8(2H, s), 4.0(2H, t), 7.0(1H, m), 7.4(2H, m),7.9(1H, d).

EXAMPLE 54 A=CH₂ CO₂ CHMe₂, B=H

Purified by chromatography on silica gel (Varian Bond Elut S1 silicagel) using a gradient of methanol in dichloromethane containing 1%ammonia (density 0.88 g/cm³) as eluent to give a gum, NMR: 1.2(6H, d),1.3(1H, m), 1.6(1H, m), 1.8-2.0(3H, m), 2.7(4H, m), 2.9(1H, d), 3.1(1H,d), 3.8(2H, s), 4.9(1H, m), 5.6(1H, s), 7.2-7.4(4H, m).

The compound of formula 2 (Z=iodo) used as starting material wasprepared as follows.

A solution of 2-(2-iodophenyl)acetic acid (0.50 g) and propan-2-ol(0.142 ml) in dry dimethylformamide (10 ml) was treated with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.458 g)with stirring at ambient temperature under an atmosphere of argon. After18 hours the reaction mixture was diluted with ethyl acetate (50 ml) andwashed with water (3×50 ml) and brine. The aqueous layers wereback-extracted with ethyl acetate (50 ml) and the organic layers werecombined, dried (MgSO₄) and evaporated. The residue was purified bychromatography on silica gel (Varian Band Elut S1 silica gel) elutingwith dichloromethane to give 2-propyl 2-(2-iodophenyl)acetate (232 mg)as a yellow oil, NMR: 1.2(6H, d), 3.8(2H, s), 4.9(1H, m), 7.0(1H, m),7.4(2H, d) and 7.85(1H, d).

EXAMPLE 55 A=allyl, B=CH₂ CH(CH₃)CO₂ CH₃

Purified by column chromatography on alumina (Fluka 507C Neutral) usinga 19:1 (v/v) mixture of ethyl acetate and methanol as eluent to give anoil; NMR(CDCl₃): 1.12(3H,d), 1.40-1.55(1H,m), 1.57-1.75(1H,m),1.90-2.15(3H,m), 2.30(1H,bs), 2.57-2.76(2H,m), 2.78-3.02(5H,m),3.06(1H,d), 3.31(1H,d.d), 3.49(2H,d), 3.62(3H,s), 4.98-5.11(2H,m),5.87-6.02(1H,m), 6.97(2H,m) and 7.32(1H,d): m/z 368(M+H).

The compound of formula 2 (Z=trifluoromethylsulphonyloxy) was preparedas follows.

A solution of methyl trans 2-methyl-3-(4-hydroxyphenyl)cinnamate (2.79g) (JAm Chem. Soc. 72, 2619, 1950) in ethyl acetate (55 ml) washydrogenated at ambient temperature/atmospheric pressure over a 10%palladium/carbon catalyst. The catalyst was removed by filtration andthe filtrate was evaported. The residue was purified by flash-columnchromatography on silica gel using a 7:3(v/v) mixture of hexane andethyl acetate as eluent to give methyl2-methyl-3-(4-hydroxyphenyl)propionate (2.45 g) as a colourless oil:NMR(CDCl₃): 1.15(3H,d), 2.63(2H,m), 2.92(1H,q), 3.60(3H,s), 5.05(1H,bs),6.71(2H,d) and 7.00(2H,d).

Methyl 2-methyl-3-(4-allyloxyphenyl)propionate m/z 235(M+H) was preparedfrom methyl 2-methyl-3-(4-hydroxyphenylpropionate using the methoddescribed in Example 1 for the preparation of ethyl3-(4-allyloxyphenyl)propionate. Methyl2-methyl-3-(3-allyl-4-hydroxyphenyl)propionate was prepared from methyl2-methyl-3-(4-allyloxyphenyl)propionate using the method described inExample 1 for the preparation of ethyl3-(3-allyl-4-hydroxyphenyl)propionate. The product was isolated as anorange oil; NMR(CDCl₃): 1.13(3H,d), 2.40-2.73(2H,m), 2.92(1H,q),3.37(2H,d), 3.63(3H,s), 4.91(1H,s), 5.03-5.18(2H,m), 5.89-6.10(1H,m),6.70(1H,m) and 6.91(2H,m); m/z 235(M+H).

The method described in Example 1 for the preparation of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate was used toconvert methyl 2-methyl-3-(3-allyl-4-hydroxyphenyl)propionate to methyl2-methyl-3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate:NMR(CDCl₃) 1.18(3H,d), 2.70(2H,m), 3.01(1H,m), 3.42(2H,d), 3.62(3H,s),5.13(2H,m), 5.90(1H,m), 7.08(2H,m) and 7.16(1H,d), m/z 366(M+H).

EXAMPLE 56 A=allyl, B=CH₂ CH₂ CO₂ CH₂ CH₂ OCH₃

Purified flash chromatography on silica gel using a 19:1 (v/v) mixtureof ethyl acetate and methanol as eluent to give a solid, m.p. 70-72° C.;NMR(CDCl₃): 1.37-1.52(1H,m), 1.60-1.78(1H,m), 1.93-2.18(3H,m),2.62(2H,t), 2.76-2.98(6H,m), 3.02-3.17(1H,m), 3.28-3.41(4H, m+s),3.45-3.60(4H,m), 4.21(2H,m), 4.98-5.10(2H,m), 5.88-6.02(1H,m),6.98-7.06(2H,m) and 7.32(1H,d), m/z 398(M+H).

The compound of formula 2 (Z=trifluoromethylsulphenyloxy), was preparedas follows.

3-Allyl-4-hydroxyphenyl propionic acid (1.1 g) was treated with2-methoxyethanol (10 ml) containing concentrated sulphuric acid (0.1 ml)for 5 hours at 100° C. The methoxyethanol was evaporated and the residuetreated with saturated sodium bicarbonate (25 ml). The aqueous mixturewas extracted with ether (3×25 ml). The ether extracts were combined,washed with saturated brine (1×25 ml), dried (MgSO₄) and evaporated. Theresidual oil was purified by flash column chromatography on silica gelusing a 4:1 (v/v) mixture of hexane and ethyl acetate to givemethoxyethyl 3-(3-allyl-4-hydroxyphenyl)propionate (915 mg) as a paleyellow oil; NMR(CDCl₃): 2.61(2H,t), 2.87(2H,t), 3.38(3H,s), 3.57(2H,t),4.21(2H,t), 4.98(1H,s), 5.08-5.18(2H,m), 5.92-6.08(1H,m), 6.71(1H,m) and6.93(2H,m): m/z 265(M+H).

The triflate was prepared as in Example 1 using methoxyethyl3-(3-allyl-4-hydroxyphenyl)propionate in place of ethyl3-(3-allyl-4-hydroxyphenyl)propionate.

Methoxyethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionatewas obtained as an oil; NMR(CDCl₃) 2.65(2H,t), 2.93(2H,t), 3.38(3H,s),3.95(2H,d), 3.57(2H,m), 4.21(2H,m), 5.07-5.20(2H,m), 5.82-5.98(1H,m) and7.15(3H,m).

EXAMPLE 57 A=allyl, B=CH₂ OCH₂ CO₂ Me

Obtained as an oil, NMR(CDCl₃): 1.33-1.50(1H,m), 1.57-1.75(1H,m),1.95-2.15(3H,m), 2.25-2.60(1H,m, exchangeable) 2.74-3.00(4H,m),3.08(2H,d), 3.32(1H,d.d), 3.52(2H,d), 3.75(3H,s), 4.10(2H,s),4.60(2H,s), 5.06(2H,m), 5.95(1H,m), 7.18(2H,m) and, 7.38(1H,d); m/z370(M+H).

The compound of formula 2 (Z=trifluoromethylsulphonyloxy), methyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)methyloxyacetate, wasprepared as follows. Allyl bromide (4.4 g) was added to a stirredsuspension of 4-hydroxybenzyl alcohol (4.34 g) and potassium carbonate(5.00 g) in butanone (40 ml). The reaction mixture was heated at refluxfor 18 hours. The reaction mixture was cooled and then filtered. Thefiltrate was evaporated to give an oil which was purifed by flash columnchromatography on silica gel using a 4:1 (v/v) mixture of hexane andethyl acetate as eluent to give 4-allyloxybenzyl alcohol (4.50 g) as apale yellow oil; NMR(CDCl₃): 1.81(1H,t), 4.48-4.65(4H,m),5.22-5.48(2H,m), 6.05(1H,m), 6.90(2H,m) and 7.25(2H,m), m/z 164(H).

Sodium hydride (1.20 g; 60% dispersion in oil) was added over a periodof 10 minutes to a stirred solution of 4-allyloxybenzyl alcohol (4.60 g)in DHF (20 ml) at 0° C. under an atmosphere of argon. After 0.5 hours, asolution of methylchloroacetate (3.30 g) in DMF (10 ml) was added over aperiod of 0.25 hours. The reaction mixture was stirred for 40 hours atambient temperature. Water (300 ml) was added and the mixture extractedwith ethyl acetate (3×100 ml). The ethyl acetate extracts were combined,washed with brine (2×100 ml), dried (MgSO₄) and evaporated. The residuewas purified by flash column chromatography on silica gel using a 9:1(v/v) mixture of hexane/ethyl acetate to give 4-allyloxyphenylmethyloxyacetate (2.42 g) as a colourless oil; NMR(CDCl₃): 3.75(3H,s),4.07(2H,s), 4.52(4H,m), 5.36(2H,m), 6.10(1H,m), 6.88(2H,m) and7.28(2H,m); m/z 236(H).

A mixture of methyl 4-allyloxyphenylmethyloxyacetate (2.00 g) anddiphenyl ether (14 ml) was heated at 200° C. in an atmosphere of argonfor 9 hours. The mixture was cooled to ambient temperature and purifiedby flash column chromatography on silica gel using a 4:1 (v/v) mixtureof hexane and ethyl acetate as eluent to give methyl(3-allyl-4-hydroxyphenyl)methyloxyacetate (435 mg) as a colourless oil;NMR(CDCl₃): 3.38(2H,d), 3.75(3H,s), 4.07(2H,s), 4.52(2H,s), 5.12(2H,m),6.00(1H,m), 6.78(1H,m) and 7.08(2H,m); m/z 236(M).

Trifluoromethane sulphonic anhydride (0.33 ml) was added over a periodof 0.1 hours to a stirred solution of the above phenol (414 mg) inpyridine (2 ml) at 0° C. under an atmosphere of argon. After 18 hours,water (30 ml) was added. The aqueous phase was extracted with ethylacetate (3×20 ml). The ethyl acetate extracts were combined, washed with1M aqueous hydrochloric acid (3×20 ml), brine (2×30 ml), dried (MgSO₄)and evaporated. The residue was purified by flash column chromatographyon silica gel using a 19:1 (v/v) mixture of hexane and ethyl acetate aseluent to give methyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)methyl oxyacetate (437mg) as a colourless oil; NMR(CDCl₃): 3.45(2H,d), 3.78(3H,s), 4.12(2H,s),4.60(2H,s), 5.14(2H,m), 5.90(1H,m) and 7.27(3H,m).

EXAMPLE 58 A=allyl, B=CH₂ CH₂ CON(Et)₂

Purified by flash chromatography on silica gel using a 90:9:1 (v/v/v)mixture of ethyl acetate/methanol/ammonia as eluent to give an oil;NMR(CDCl₃): 1.10(6H,t), 1.33-1.52(1H,m), 1.52-1.72(1H,m),1.92-2.16(3H,m), 2.55(2H,m), 2.75-3.03(7H,m), 3.08-3.42(5H,m),3.50(2H,d), 4.97-5.11(2H,m), 5.85-6.05(1H,m), 7.02(2H,m) and 7.32(1H,d),m/z 395(M+H).

The compound of formula 2 (Z=trifluoromethylsulphonyloxy), N,N-diethyl3-(3-allyl-4-trifluromethylsulphonyloxyphenyl)propionamide, used asstarting was prepared from N,N-diethyl 3-(4-hydroxyphenyl)propionamideusing the procedure described in Example 1 for the preparation of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate via thefollowing intermediates

a) N,N-diethyl 3-(4-allyloxyphenyl)propionamide, a colourless oil;NMR(CDCl₃): 1.10(5H,m), 2.53(2H,m), 2.90(2H,m), 3.22(2H,q), 3.37(2H,q),4.51(2H,d.t), 5.23-5.47(2H,m), 5.95-6.15(1H,m), 6.83(2H,m) and7.12(2H,m), m/z 262(M+H).

b) N,N-diethyl 3-(3-allyl-4-hydroxyphenyl)propionamide, a pale yellowoil; NMR(CDCl₃): 1.10(6H, m), 2.55(2H,m), 2.88(2H,m), 3.22(2H,q),3.38(4H,q), 5.06-5.20(2H,m), 5.61(1H,br.d), 5.90-6.10(1H,m), 6.75(1H,m)and 6.97(2H,m), m/z 262(M+H).

c) N,N-diethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionamide, a pale yellow oil; m/z 394(M+H).

EXAMPLE 59 A=CH₂ OCH₂ C.tbd.CCH₃, B=H

Purified by chromatography on silica gel (Varian Bond Elut S1 silicagel) using a gradient of 0 to 5% methanol in dichloromethanol as eluentto give a gum, NMR(CDCl₃): 1.45(1H,m), 1.7(1H,m), 1.88(3H,t),2.09(3H,m), 2.88(4H,m), 3.1(1H,d), 3.35(1H,d), 4.2(2H,q), 4.7(2H,s),7.3(2H,m) and 7.42(2H,t); m/z 310 (M+H).

The compound of formula 2 (Z=iodo) used as starting material wasprepared in a similar manner to the compound of formula 2 described inExample 60 but using 2-iodobenzyl chloride in place of 2-iodobenzylalcohol and 2-butyn-1-ol in place of allyl bromide. The reaction mixturewas used without purification.

EXAMPLE 60 A=CH₂ OCH₂ CH═CH₂, B=H

Purified by chromatography on silica gel (Varian Bond Elut S1 silicagel) using a gradient of 0 to 5% methanol in dichloromethane as eluentto give a gum, NMR(CDCl₃): 1.5(1H,m), 1.72(1H,m), 2.12(3H,m), 2.9(4H,t),3.05(2H,m), 3.15(1H,d), 3.38(1H,d), 4.05(2H,m), 4.62(2H,s), 5.25(2H,m),5.95(1H,m), 7.22(1H,t), 7.35(1H,t), 7.45(2H,q); m/z 298(M+H).

The compound of formula 2 (Z=iodo) was prepared as follows.

Sodium hydride (220 mg of 60% dispersion in mineral oil) was added to astirred solution of 2-iodobenzylalcohol (1.17 g) in dimethylformamideunder an atmosphere of argon. Allyl bromide (520 μl) was added to thestirred suspension and the mixture was stirred at ambient temperaturefor 16 hours and then heated at 60° C. for 2 hours. The mixture was usedwithout purification.

EXAMPLE 61 A=CH₂ OCH₂ CH₃, B=H

Purifed by chromatography on silica gel (Varian Bond Elut S1 silica gel)using a gradient of 0 to 5% methanol in dichloromethane as eluent togive a gum, NMR(CDCl₃): 1.25(3H,t), 1.45(1H,m), 1.7(1H,m), 2.08(3H,m),2.85(4H,t), 3.1(1H,d), 3.33(1H,d), 3.59(2H,q), 4.65(2H,s), 7.2(1H,t),7.32(1H,t), 7.42(2H,q); m/z 286 (M+H)

The compound of formula 2 (Z=iodo) was prepared using the proceduredescribed in Example 60 for the compound of formula 2 but using ethyliodide in place of allyl bromide.

The reaction mixture was used without purification.

EXAMPLE 62 A=CH₂ OCOCH₂ CH₃, B=H

Purified by chromatography on silica gel (Varian Bond Elut S1 silicagel) using a 0 to 5% gradient of methanol in dichloroethane as eluent togive a gum; NMR(CDCl₃): 1.16(3H,t), 1.45(1H,m), 1.69(1H,m), 2.0(3H,m),2.4(2H,q), 2.87(4H,m), 3.07(1H,d), 3.84(1H d of d), 5.27(2H,d),7.25-7.45(4H,m). m/z 314 (M+H).

The compound of formula 2 (Z=iodo) was prepared as follows.

Propionyl chloride (505 mg) was added to a stirred solution of2-iodobenzyl alcohol (1.17 g) and pyridine (474 mg) in dichloromethane(10 ml). The mixture was stirred at ambient temperature for 16 hours.The reaction mixture was evaporated and dimethylformamide (15 ml) wasadded to the residue. The mixture was used without purification.

EXAMPLE 63 A=CO₂ CH(Me)Et, B=OCH₂ CH₂ OCH₃

Purified by chromatography on silica gel (Varian Bond Elut S1 silicagel) using a 0 to 10% gradient of methanol in dichloromethane to give onoil; NMR(CDCl₃): 0.91(3H,t), 1.30(3H,d), 1.4-1.8(2H,m), 1.92(1H,m),2.67(2H,t), 2.83(1H,d), 3.10(1H,d), 3.68(2H,m), 4.15(2H,m), 4.95(1H,m),7.15(1H d of d), 7.18(1H,d), 7.43(1H,d); m/z 4102 (M+H).

The compound of formula 2 (Z=trifluoromethylsulphonoxy) used as startingmaterial was prepared in a similar manner to that described in Example64 but sec-butanol was used in place of ethanol. The compound of formula2 was obtained as an oil; NMR: 0.90(3H,t), 1.30(3H,d), 1.70(2H,m),3.3(3H,s), 3.67(2H,m), 4.2(2H,m), 5.02(1H,m), 7.35(1H d of d),7.48(2H,m); m/z 400(M) via the corresponding phenol; NMR: 0.92(3H,t),1.32(3H,d), 1.7(2H,m), 3.62(2H,m), 4.05(2H,m), 5.05(1H,m), 6.92(1H,d),7.2(1H d of d), 7.28(1H,d), 10.2(1H,s); m/z 268(M).

EXAMPLE 64 A=CO₂ Et, B=OCH₂ CH₂ OCH₃

Purified by trituration with acetonitrile and diethyl ether to give asolid, m.p. 153.5-154.5° C.; NMR(CDCl₃): 1.38(3H,t), 1.64(1H,m),1.5-1.4(1H,m), 1.8-1.95(1H, broad) 2.08(3H,m), 2.65(4H,m), 3.33(1H,d),3.04(1H,d), 3.45(3H,s), 3.75(2H,m), 4.15(2H,m), 4.35(2H,q), 7.0(1H, d ofd) and 7.42(2H,m).

The compound of formula 2 (Z=trifluoromethylsulphonyloxy) was preparedas follows.

Sodium chlorite (8.08 g) was added over a period of 30 seconds to astirred solution 2-hydroxy-5-(2-methoxyethoxy)benzaldehyde (see Example41) and sodium methoxide in methanol (25% by weight solution, 9.68 ml)in dimethylsulphoxide (350 ml) at 15° C. After warming to roomtemperature and stirring for 3 hours the mixture was added to water (600mls), acidified with 2M aqueous hydrochloric acid, and extracted withdiethyl ether (4×250 mls). The ethereal extracts were combined, washedwith water (2×100 ml), dried (MgSO₄) and evaporated. The residue wascrystallised from toluene to give 2-hydroxy-5-(2-methoxyethoxy)benzoicacid (4.1 g) as solid m.p. 115-116° C.; NMR 3.3(3H,s), 3.65(2H,m),4.05(2H,m), 6.9(1H,d), 7.15(1H, d of d), 7.25(1H,d); m/z 213(M+H).

Concentrated sulphuric acid (0.5 ml) was added to a stirred solution of2-hydroxy-5-(2-methoxyethoxy)benzoic acid (2 g) in ethanol (50 ml). Themixture was heated at reflux for 12 hours. The reaction mixture wasadded to sodium hydrogen carbonate solution (5% by weight in water, 200ml) and the aqueous mixture was extracted with ethyl acetate (4×50 ml).The organic extracts were combined, washed with water (50 ml), brine,(50 ml), dried (MgSO₄) and evaporated to give2-ethoxycarbonyl-4-(2-methoxyethoxy)phenol (1.85 g) as an oil; NMR:1.35(3H,t), 3.31(3H,s), 3.6(2H,m), 4.0(2H,m), 4.3(2H,q), 6.9(1H,d),7.18(1H d of d), 7.2(1H,d); m/z 241(MH). This was converted into thetrifluoromethane sulphonate ester using an analogous procedure to thatdescribed in Example 1 for the preparation of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxy)propionate. There was thusobtained after chromatography on silica gel (Varian bond elut S1 silicagel) using a gradient of 5 to 25% ethyl acetate in hexane as eluent asan oil; NMR(₆): 1.3(3H,t), 3.3(3H,s), 3.62(2H,m), 4.2(2H,m), 4.34(2H,q),7.35(1H, d of d), 7.49(2H,m); m/z 373(M+H).

EXAMPLE 65

Using the procedure described in Example 1 but using(-)-3-ethynyl-3-hydroxyquinuclidine in place of3-ethynyl-3-hydroxyquinuclidine there was obtained (-)-3-2-(2-allyl-4-(2-ethoxycarbonylethyl)phenyl)ethynyl!quinuclidin3-ol as anoil.

The (-)-3-ethynyl-3-hydroxyquinuclidine used as starting material wasprepared as follows.

A solution of (±)-3-ethynyl-3-butyryloxy quinuclidine (4.42 g) indeionised water (700 ml) containing methanol (35 ml) was adjusted to pH7.0 using 0.1M aqueous sodium hydroxide solution (dispensed by a pHautotitrator). A suspension of pig liver esterase (3.0 ml, 3450 units,in 3.2M aqueous ammonium sulphate solution at pH 8; Sigma ChemicalCompany Ltd) was added to the reaction mixture and the mixture stirredat ambient temperature for 46 hours whilst maintaining the pH at 7.0using 0.1M aqueous sodium hyroxide solution (dispensed from a pHautotitrater). During this period 112.5 ml of the sodium hydroxidesolution was consumed, indicating that the hydrolysis was 56% complete.The pH of the reaction mixture was adjusted to 2.52 using 2M aqueoushydrochloric acid and the mixture stirred for 20 minutes. 2M aqueoussodium hydroxide solution was added to the mixture to give a pH of 7.01and the mixture extracted with diethyl ether (12×150 ml). The diethylether extracts were combined, dried (MgSO₄) and evaporated to give anoil (2.43 g) containing (-)-3-ethynyl-3-butyryloxyquinuclidine and somebutyric acid.

The above oil containing(-)-3-ethynyl-3-butyryloxyquinuclidine wastreated with a solution of potassium hydroxide (2.24 g) in methanol (50ml). The mixture was stirred at ambient temperature for 2 hours. Themixture was evaporated and deionised water (2 ml) was added to theresidue to give a solid. The solid was collected by filtration, washedwith water (2×2 ml) and dried under vacuum over phosporus pentoxide togive (-)-3-ethynyl-3-hydroxyquinuclidine (611 mg) as a solid, m.p.199-202° C., α!¹⁹ _(D) =-56.1° (C=1.02, methanol).

EXAMPLE 66

Using the procedure described in Example 1 but using(+)-3-ethynyl-3-hydroxyquinuclidine in place of3-ethynyl-3-hydroxyquinuclidine there was obtained (+)-3- 2-(2-allyl-4(2-ethoxycarbonylethyl)phenyl)ethynyl!quinuclidin-3-ol as an oil, α!²⁵D=+21.8 (C=0.316, ethanol).

The (+)-3-ethynyl-3-hydroxyquinuclidine was prepared as follows.

A solution of (±)-3-ethynyl-3-butyryloxyquinuclidine (4.42 g) indeionised water (700 ml) containing methanol (35 ml) was adjusted to pH7.0 using an 0.1M aqueous sodium hydroxide solution (dispensed by a pHautotitrater). A suspension of pig liver esterase (8.0 ml, 9200 units,in3.2M aqueous ammonium sulphate solution at pH 8; S1 gma Chemical CompanyLtd) was added to the reaction mixture and the mixture was stirred atambient temperature whilst maintaining the pH at 7.0 using 0.1M aqueoussodium hydroxide solution (dispensed by a pH autotitrater). After 5.5hours, 7.3 ml of the sodium hydroxide solution had been consumed,indicating that the hydrolysis was 35% complete. The pH of the reactionmixture was adjusted to 2.5 using 2H aqueous hydrochloric acid and themixture was stirred for 10 minutes. 2M aqueous sodium hydroxide solutionwas then added to the mixture to give a pH of 7.05 and the mixtureextracted with diethyl ether (3×200 ml, followed by 12×150 ml). Theaqueous phase was separated, and freeze dried over a period of 48 hoursto give a solid which was dissolved in deionised water (30 ml). Thesolution was filtered and the filtrate was basified to pH 9 using 10.8Msodium hydroxide solution to give a solid. The solid was collected byfiltration to give (+)-3-ethynyl-3-hydroxyquinuclidine, (554 mg), m.p.204-207° C., α!²⁰ _(D) =+54.5° (C=0.99, methanol).

The (±)-3-ethynyl-3-butyryloxyquinuclidine used as starting material wasprepared as follows.

A solution of n-butyl lithium (100 ml of a 2M solution in pentane) wasadded portion-vise over a period of 20 minutes to a stirred solution ofethynyltrimethylsilane (19.6 g) in dry tetrahydrofuran (400 ml) at -70°C. The mixture was stirred for 1 hour at -70° C. A solution of3-quinuclidinone (2.4 g) in dry tetrahydrofuran (100 ml) was then addedand the mixture stirred for 1 hour at -70° C. Methanol (1 ml) was thenadded to the mixture and the mixture allowed to warm to ambienttemperature. The solvents were removed by evaporation. Methanol (500 ml)and potassium carbonate (40 g) were added to the residue and the mixturewas stirred for 1 hour. The solvent was removed by evaporation. Theresidue was triturated with water (500 ml) and then dried in vacuo togive 3-ethynyl-3-hydroxy-quinuclidine as a solid, m.p. 193-197° C.;NMR(DMSO-d₆): 1.5-1.3(1H,m), 1.4-1.6(1H,m), 1.7-1.95(3H,m),2.55-2.8(5H,m), 2.95(1H,d), 3.3(1H,d) and 5.4(1H,s); m/z 152 (M+H).

A mixture of (±)-3-ethynyl-3-hydroxyquinuclidine (15.1 g) and butyricanhydride (60 ml) was stirred at 120° C. for 5 hours. The reactionmixture was cooled to ambient temperature, added to a saturated aqueoussolution of sodium carbonate (11) and stirred for 3 hours. The mixturewas extracted with diethyl ether (3×10 ml). The diethyl ether extractswere combined, washed with saturated aqueous sodium carbonate solution,dried (MgSO₄) and evaporated to give(±)-3-ethynyl-3-butyryloxyquinuclidine as an oil, NMR(200 MHz, DMSOd₆):0.90(3H,t), 1.40(1H,m), 1.57(4H,m), 1.85(1H,m), 2.28(3H,m),2.66(4H,m),.3.03(1H,d), 3.18(1H,d) and 3.55(1H,s).

EXAMPLE 67

3- 2- 2-allyl-4-(2-ethoxycarbonylethyl)-phenyl!ethynyl!quinuclidin-3-ol(300 mg) was added to a stirred solution of sodium hydroxide pellets(150 mg) in a mixture of ethanol (6 ml) and water (3 ml) at ambienttemperature. After 15 hours, the solution was filtered and the filtratewas evaporated. The residue was stirred with water (5 ml) and 1M aqueoushydrochloric acid (6 ml) was then added. The mixture was evaporated andthe residue azeotroped with toluene (2×10 ml). The residue was treatedwith dry acetone (10 ml) and filtered. The insoluble residue was washedwith acetone (5 ml). The filtrate and washings were combined, evaporatedand the residue triturated with ether. Evaporation of the ether gave 3-2- 2-allyl-4-(2-carboxyethyl)-phenyl)ethynyl!quinuclidin-3-olhydrochloride salt as a solid (247 mg), m.p. 41.4° C. (dec), NMR( CD₃ !₂SO/CD3COOD): 1.60-1.88(1H,m), 1.92-2.10(2H,m), 2.10-2.40(3H,m),2.52(2H,t), 2.84(2H,t), 3.10-3.60(8H,m), 5.08(2H,m), 5.98(1H,m),7.12(2H,m) and 7.37(1H,d); m/z 340(M+H).

EXAMPLE 68

Using the procedure described in Example 67 but using (+)-3-2-allyl-4-(2-ethoxycarbonylethyl)phenyl)ethynyl!quinculidin-3-ol asstarting material, there was thus obtained (+)-3-2-(2-allyl-4-(2-carboxyethyl)phenyl)ethynyl)quinuclidine-3-olhydrochloride, as a solid, m.p. 161-163° C., NMR(DMSOd₆ /CD₃ COOD):1.60-1.88(1H,m), 1.92-2.10(2H,m), 2.10-2.40(3H,m), 2.52(2H,t),2.84(2H,t), 3.10-3.60(8H,m), 5.08(2H,m), 5.98(1H,m), 7.12(2H,m) and7.37(1H,d); m/z 340(M+H).

EXAMPLE 69

Using the procedure described in Example 67 but using (-)-3-2-allyl-4-(2-ethoxycarbonylethyl)phenyl)ethynyl!quinuclidin-3-ol asstarting material, there was thus obtained (-)-3-2-(2-allyl-4-(2-carboxyethyl)phenyl)ethynyl)quinuclidin-3-olhydrochloride as a solid, 161-163° C.; NMR: 1.60-1.88(1H,m),1.92-2.10(2H,m), 2.10-2.40(3H,m), 2.52(2H,t), 2.84(2H,t),3.10-3.60(8H,m), 5.08(2H,m), 5.98(1H,m), 7.12(2H,m) and 7.37(1H,d), m/z340(M+H).

EXAMPLE 70

Using the procedure described in Example 1 but using4-(methoxycarbonylmethyl)iodobenzene as starting material in place ofethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate and3-ethenyl-3-hydroxyquinuclidine in place of3-ethynyl-3-hydroxyquinuclidine, there was obtained, afterrecrystallisation from ethyl acetate, 3-2-(4-methoxycarbonylmethoxyphenyl)vinyl!quinculdine-3-ol as a solid,m.p. 169-170° C., NMR(CDCl₃): 1.32-2.20(6H,s quinuclidine+OH at 1.9),2.7-3.15(6H,m), 3.8(3H, d), 4.65(2H,s), 6.3-6.5(2H,m), 6.84-7.38(4H,m).

EXAMPLE 71

Using a similar procedure to that described in Example 21 but using3-(4- 2-methoxyethoxy!phenoxymethyl)-3-hydroxyquinuclidine boranecomplex as starting material there was obtained 3-(4-2-methoxyethoxy!phenoxymethyl)quinuclidin-3-ol as a solid, m.p. 93-95°C., NMR: 1.5-1.8(1H,m), 1.7-2.0(2H,m), 2.1-2.4(2H,m), 2.9-3.4(9H,m),3.55-3.65(2H,m), 3.9-4.1(4H,m), 5.45-5.55(1H,s), 6.8-6.95(4H,s) and10.0-10.6(1H,br).

The 3-(4- 2-methoxyethoxy!phenoxymethyl)-3-hydroxyquinuclidine boranecomplex used as starting material was prepared as follows.

Solid potassium carbonate (0.42 g) was added to a solution of4-methoxyethoxyphenol (0.44 g) and 3-methylenequinuclidine oxide boranecomplex (0.31 g) in dry dimethylformamide (1 ml) under an atmosphere ofargon. The mixture was stirred for 6 hours at 75° C. The mixture waspoured into water (3 ml) and extracted with ethyl acetate (3×3 ml). Theethyl acetate extracts were combined, washed with water (4×2.5 ml),dried (Na₂ SO₄) and evaporated. The residue was crystallised from etherto give 3-(4- 2-methoxyethoxy!phenoxymethyl)-3-hydroxyquinuclidineborane complex as a colourless solid (0.53 g), m.p. 107-109° C.;NMR(CDCl₃): 0.5-2.5(3H,br), 1.5-1.7(1H,m), 1.75-1.9(2H,m) 2.2-2.4(2H,m),2.7-2.75(1H,s), 2.8-3.25(6H,m), 3.4-3.5(3H,s), 3.7-3.8(2H,m),3.8-4.0(2H,q), 4.05-4.15(2H,m), 6.8-6.95(4H,m).

EXAMPLE 72

Using a similar procedure to that described in Example 21 but using3-(4-ethoxycarboxyethylphenoxymethyl)-3-hydroxyquinuclidine boranecomplex as starting material there was obtained3-(4-ethoxycarboxyethylphenoxymethyl)quinuclidine-3-ol as a solid m.p.75-77° C., NMR(DMSOd₆): 1.2-1.3(3H,t), 1.3-1.45(1H,m), 1.5-1.65(2H,m),2.05-2.2(2H,m), 2.3-2.65(1H,br), 2.5-3.1(10H,m), 3.8-4.05(2H,q),4.05-4.2(2H,q), 6.8-6.9(2H,d), 7.1-7.2(2H,d).

The 3-(4- 2-ethoxycarboxyethyl!phenoxymethyl)-3-hydroxyquinuclidineborane used as starting material was prepared from 4-ethoxycarbonylethyl phenol using an analogous procedure to that described in Example71 for the preparation of the borane starting material.

The procedure described in Example 71 was repeated using4-ethoxycarbonylethylphenol (0.47 g) instead of 4-methoxyethoxyphenol.There was thus obtained 3-(4-2-ethoxycarbonylethyl!phenoxymethyl-3-hydroxyquinuclidine borane complexas a yellow oil (0.74 g).

EXAMPLE 73

Using a similar procedure to that described in Example 21, but using3-(2-allyl-4- 2-ethoxycarbonylethyl!phenoxymethyl)-3-hydroxyquinuclidine borane complex as starting material there was obtained3-(2-allyl-4- 2-ethoxycarbonylethyl!phenoxymethyl)quinclidine-3-ol as asolid, m.p. 160-162° C., NMR(DMSOd₆ /CD₃ COOD): 1.0-1.15(3H,t),1.55-1.75(1H,m), 2.1-2.35(2H,m), 2.6-2.8(2H,t), 3.0-3.4(8H,m),3.85-4.1(4H,m), 4.9-5.05(2H,m), 5.8-6.0(1H,m), 6.6(1H,s),6.75-6.85(1H,d), 6.9-7.0(2H,m).

The 3-(2-allyl-4-2-ethoxycarbonylethyl!phenoxymethyl)-3-hydroxyquinuclidine boranecomplex used as starting material was prepared from2-allyl-4-ethoxycarbonylethylphenol (0.5 g) using a procedure analogousto that described in Example 74 for the preparation of the boranestarting material. There was thus obtained 3-(2-allyl-4-2-ethoxycarbonylethyl!phenoxymethyl)-3-hydoxyquinuclidin e boranecomplex as an oil (0.87 g); NMR(CDCl₃): 0.5-2.5(3H,br), 1.15-1.3(3H,t),1.5-1.7(1H,m), 1.7-1.9(2H,m), 2.2-2.4(2H,m), 2.5-2.65(2H,t),2.7-2.8(1H,s), 2.8-3.3(8H,m), 3.3-3.4(2H,d), 3.8-4.05(2H,q),4.05-4.2(2H,q), 4.9-5.1(2H,m), 5.85-6.1(1H,m), 6.7-6.8(1H,d) and6.9-7.1(2H,m).

EXAMPLE 74

Using a similar procedure to that described in Example 21 but using3-(2-allyl-4- 2-methoxyethoxy!phenoxymethyl)-3-hydroxyquinuclidineborane complex as starting material, there was obtained 3-(2-allyl-4-2-methoxyethoxy!phenoxymethyl)quinuclidine-3-ol is a solid, m.p. 58-60°C., NMR: 1.3-1.45(1H,m), 1.55-1.7(2H,m), 2.05-2.2(2H,m),2.45-2.65(1H,br), 2.6-3.1(6H,m), 3.3-3.4(2H,m), 3.45(3H,s),3.7-3.75(2H,m), 3.75-4.05(2H,q), 4.05-4.1(2H,m), 4.95-5.1(2H,m),5.85-6.05(1H,m), 6.7-6.8(3H,m).

The 3-(2-allyl-4- 2-methoxyethoxy!phenoxymethyl)-3-hydroxyquinuclidineborane used as starting material was prepared from2-allyl-4-methoxyethoxyphenol (0.42 g) using a method analogous to thatdescribed for the preparation of the borane starting material in Example71.

There was thus obtained 3-(2-allyl-4-2-methoxyethoxy!phenoxymethyl)-3-hydroxyquinuclidine borane complex asan oil (0.48 g). NMR(CDCl₃): 0.7-2.4(3H,br), 1.6-1.7(1H,m),1.7-1.85(2H,m), 2.2-2.4(2H,m), 2.75(1H,s), 2.8-3.25(6H,m),3.3-3.4(2H,d), 3.45(3H 3.7-3.75(2H,m), 3.8-4.0(2H,q), 4.05-4.1(2H,m),4.9-5.1(2H,m), 5.85-6.0(1H,m) and 6.7-6.8(3H,m).

EXAMPLE 75

The procedure described in Example 7 was repeated using4-bromo-2-methoxyphenol in place of 4-iodophenol. There was thusobtained, after purification by flash chromatography on silica gel usinga gradient of 0 to 20% methanol in dichloromethane containing 1% ammonia(density, 0.88 g/cm³) followed by recrystallisation from acetonitrile,3- 2-(3-methoxy-4-(2-methoxyethoxy)phenyl)ethynyl!quinuclidin-3-ol as asolid, m.p. 130-131° C., NMR: 1.21-1.40(1H,m), 1.47-1.65(1H,m),1.77-2.00(3H,m), 2.66(4H,t), 2.75-3.12(2H,q), 3.60-3.70(2H,m),3.76(3H,s), 4.02-4.12(2H,m), 5.49(1H,s) and 6.87-6.98(3H,m).

EXAMPLE 76

The procedure described in Example 7 was repeated using4-bromo-2-fluorophenol in place of 4-iodophenol. There was thus obtained3- 2-(3-fluoro-4-(2-methoxyethoxy)phenyl)ethynyl!quinuclidin-3-ol as asolid, m.p. 136-139° C., NMR: 1.21-1.43(1H,m), 1.49-1.70(1H,m),1.75-2.00(3H,m), 2.70(4H,t), 2.75-3.15(2H,q), 3.30(3H,s),3.60-3.75(2H,m), 4.14-4.26(2H,m), 5.62(1H,s) and 7.10-7.32(3H,m).

EXAMPLE 77

The procedure described in Example 1 was repeated using methyl-3-3,5-diallyl-4-trifluoromethylsulphonyloxy)phenyl)propionate as startingmaterial in place of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxy)phenyl)propionate. There wasthus obtained, after purification by flash chromatography on silica gelusing 10% methanol in dichloromethane containing 1% ammonia (density,0.88 g/cm³) as eluent, 3-2-(2,6-diallyl-4-(2-methoxycarbonylethyl)phenyl)ethynyl!quinuclidin-3-ol.Treatment with fumaric acid gave, a solid which was recrystallised froma mixture of acetone and diethyl ether to give the hemi-fumarate salt asa solid, 140-143° C., NMR: 1.35-1.52(1H,m), 1.6-1.78(1H,m),1.85-2.1(3H,m), 2.6(2H,m), 2.6(6H,t), 3.0(1H,br), 3.2(1H,br), 3.5(4H,d),3.6(3H,s), 4.25(2H,br+H₂ O), 5.08(4H,m), 5.85-6.05(2H,m), 6.52(1H,s) and6.97(2H,s).

The methyl-3-3,5-diallyl-4-(trifluoromethylsulphonyloxy)phenyl!propionate used asstarting material was prepared as follows.

A mixture of methyl-3(3-allyl-4-hydroxyphenyl)propionate (12.3 g),anhydrous potassium carbonate (13.8 g), and allylbromide (8.64 mls) inacetone (300 ml) was stirred at ambient temperature for two days. Thereaction mixture was filtered and the residue washed with acetone. Thefiltrate and washings were combined and evaporated to givemethyl-3-(3-allyl-4-allyloxyphenyl)proprionate as a pale yellow oil(14.0 g); NMR: 2.58(2H,t), 2.75(2H,t), 3.31(2H,d), 3.55(3H,s),4.52(2H,d), 4.95-5.45(4H,m), 5.85-6.11(2H,m), 6.85(1H,d) and 7.0(2H,m).

Methyl-3-(3-allyl-4-allyloxyphenyl)propionate (4 g) was heated at 250°C. for 10 minutes and then cooled. The residue was purified by flashcolumn chromatography on silica gel using 50% ethyl acetate in n-pentaneas eluent to give methyl-3-(3, 5-diallyl-4-hydroxyphenyl)propionate (2.5g); NMR:

2.5(2H,t), 2.7(2H,t), 3.32(4H,d), 3.57(3H,s), 4.96-5.1(4H,m),5.82-6.05(2H,m), 6.75(2H,s) and 8.07(1H,s).

Trifluoromethane sulphonic anhydride (1.68 g) was added dropwise at 0-5°C. to a stirred solution ofmethyl-3(3,5-diallyl-4-hydroxyphenyl)propionate (2.5 g) in dry pyridine(20 ml). The mixture was then stirred at ambient temperature for afurther 16 hours. The pyridine was removed by evaporation. The residuewas treated with water (30 ml) and the mixture was extracted with ether(3×30 ml). The ethereal extracts were combined, washed with water (30ml), dried (MgSO₄) and evaporated. The residue was purified byfiltration through a short pad of silica gel (Merck Art 7736) using amixture of 50% ether in n-pentane as eluent to give methyl-3-3,5-diallyl-4-(trifluoromethylsulphonyloxy)phenyl!propionate (3.5 g) asa pale yellow oil; NMR: 2.52(2H,t), 2.75(2H,t), 3.34(4H,d), 3.48(3H,s),4.87-5.03(4H,m), 5.68-5.9(2H,m) and 7.03(2H,s).

EXAMPLE 78

Using the method described in Example 21, but using2-hydroxymethyl-4-(2-methoxyethoxy)phenol as starting material andomitting the step of treating with fumaric acid, there was obtained 3-2-hydroxymethyl-4-(2-methoxyethoxy)phenyloxymethyl!quinuclidin-3-ol asan oil (313 mg) NMR(CDCl₃): 1.32-1.42(1H,br), 1.61(2H,br), 2.1(2H,br),2.80(6 h,v.br), 3.4(3H,s), 3.72(2H,m), 3.83(1H,d), 4.08(3H,m),4.62(2H,q), 6.80(2H,d) and 6.90(1H,m); m/z 338(M+H).

The 2-hydroxymethyl-4-(2-methoxyethoxy)phenol used in above procedurewas prepared in the following manner.

Sodium borohydride (519 mg) was added to a solution of2-hydroxy-5-(2-methoxyethoxy)benzaldehyde (5.55 g) in ethanol (25 ml)whilst maintaining the temperature at 5° C. The resulting mixture wasstirred at 25° C. for 30 minutes. The mixture was poured into water (100ml) and acidified to pH 4 using glacial acetic acid. The mixture wasextracted with ethyl acetate (3×10 ml). The ethyl acetate extracts werecombined, washed with brine (15 ml), dried (MgSO₄) and evaporated togive an oil (4.1 g). This oil was purified by flash chromatography onsilica gel (Merck Art No 3985) using a gradient of 30 to 55% ethylacetate/hexane as eluent to give2-hydroxymethyl-4-(2-methoxyethoxy)phenol as an oil (2.67 g); NMR:3.0(3H,s), 3.6(2H,m), 3.96(2H,m), 4.45(2H,d), 4.96(1H,t), 6.64(2H,m),6.87(1H,d) and 8.84(1H,s); m/z 198(M).

The 2-hydroxy-5-(2-methoxyethoxy)benzaldehyde used as starting materialwas prepared as in example 41.

EXAMPLE 79

3- 2-(2-formyl-4-(2-methoxycarbonylethyl)phenyl!ethynyl!quinuclidin-3-ol(575 mg) was stirred with methanol (25 ml) at ambient temperature underan atmosphere of argon. Sodium borohydride (329 mg) was addedportionwise over 5 minutes to the reaction mixture and stirringcontinued at ambient temperature overnight. Water (25 ml) was added andthe mixture was extracted with ethyl acetate (25 ml). The organic phasewas separated, washed with saturated aqueous sodium carbonate (3×25 ml),water (3×25 ml), dried (MgSO₄) and evaporated. The residue was purifiedby elution through silica gel (10 g Bond elut column) with a gradient of0-30% methanol in dichloromethane to give 3-2-(2-hydroxymethyl-4-(2-methoxycarbonylethyl)phenyl)ethynyl!quinuclidin-3-ol(160 mg) as a solid, m.p. 35.8° C.; microanalysis, found: C, 69.2; H,7.5; N, 3.9% C₂₀ H₂₅ NO₄ 0.2 H₂ O requires: C, 69.2; H, 7.38; N, 4.04%;NMR(CDCl₃): 1.4(1H,m), 1.66(1H,m), 2.02(3H,m), 2.62(2H,t), 2.8(3H,m),2.95(2H,t), 3.03(1H,d), 3.27(1H,d), 3.66(3H,s), 4.75(2H,s), 7.07(1H,m)and 7.3(2H,m); m/z 344 (M+H).

EXAMPLE 80

Using the method described in Example 1, but carrying out the reactionat ambient temperature overnight and with 2-iodophenylacetonitrile (667mg) in place of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate there was thusobtained 2- 2-(2-cyanomethyl phenyl)ethynyl!quinuclidin-3-ol as a solid(292 mg), m.p. 147.1° C., microanalysis found: C, 75.6; H, 7.1; N, 10.4%C₁₇ H₁₈ N₂ O 0.25 H₂ O requires: C, 75.4; H, 6.88; N, 10.3%; NMR:1.3(1H,m), 1.59(1H,m), 1.94(3H,m), 2.69(4H,m), 2.84(1H,d), 3.17(1H,d),4.05(2H,s), 5.63(1H,s) and 7.41(4H,m); m/z 267(M+H).

EXAMPLE 81

Using the method described in Example 1 but carrying out the reaction atambient temperature overnight and with methyl3-(3-formyl-4-trifluoromethanesulphonyloxyphenyl)propionate (884 mg) inplace of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate, there wasthus obtained 3- 2-2-formyl-4-(2-methoxycarbonylethyl)phenyl)ethynyl!quinuclidin-3-ol as asolid (437 mg), m.p. 182.3° C.; microanalysis, found: C, 69.4; H, 6.8; N4.0% C₂₀ H₂₃ NO₄ 0.25 H₂ O requires: C, 69.4; H, 6.85; N, 4.05%; NMR:1.32(1H,m), 1.62(1H,m), 1.9(2H,m), 2.68(6H,m), 2.85(1H,d), 2.93(2H,t3.14(1H,d), 3.57(3H,s), 5.68(1H,s), 7.54(2H,m), 7.68(1H,m) and10.39(1H,s); m/z 342(M+H).

The methyl-3-(3-formyl-4-trifluoromethylsulphonyloxyphenyl)propionateused as starting material was prepared in an analogous manner to thepreparation of the starting material for Example 41.

EXAMPLE 82

Sodium borohydride (28.4 mg) was added to a solution of 3-2-(3-formyl-4-(2-methoxyethoxy)phenyl)ethynyl!quinuclidin-3-ol inmethanol at 0° C. The mixture was allowed to warm to ambient temperatureand stirred for 1.5 hours. The reaction mixture was poured onto water(15 ml) and the mixture extracted with ethyl acetate (3×20 ml). Theethyl acetate extracts were combined, washed with brine solution (20ml), dried (MgSO₄) and evaporated. The residue was dissolved inacetonitrile (5 ml) and diethylether was added to give, on cooling, asolid (262 mg). This solid was further purified by crystallisation fromacetonitrile to give 3-2-(2-hydroxymethyl-4-(2-methoxyethoxy)phenyl)ethynyl!quinuclidin-3-ol(217 mg) as a solid, m.p. 98.5-100.0° C.; microanalysis, found C, 67.5%;H, 7.7%, N, 6.9%, C₁₉ H₂₅ NO₄ 0.8CH₃ CN requires: C, 67.9%; H, 7.6%; N,6.9%; NMR(CDCl₃): 1.40(1H,m), 1.65(1H,m), 2.0(3H,s), 2.05(3H,m),2.8(4H,t), 3.03(1H,d), 3.28(1H,d), 3.45(3H,s), 3.75(2H,t), 4.13(2H,t),4.72(2H,s), 6.78(1H,m), 7.05(1H,d) and 7.3(1H,t); m/z 332(M+H).

EXAMPLE 83

Using a similar procedure to that described in Example 1 but using(+)-3-ethynyl-3-hydroxyquinuclidine in place of3-ethynyl-3-hydroxyquinuclidine and methyl 4-3-allyl-4-trifluoromethylsulphonyloxyphenyl)butanoate in place of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate, there wasthus obtained (+)-3-2-(2-allyl-4-(3-methoxycarbonylpropyl)phenyl)ethynyl!quinuclidin-3-ol asa gum, NMR(CDCl₃): 1.3-1.5(1H,m), 1.55-1.75(1H,m), 1.9-2.15(2H,m),2.3-2.4(2H,t), 2.6-2.7(2H,t), 2.8-3.0(4H,m), 3.0-3.15(1H,d),3.25-3.4(1H,d), 3.5-3.55(2H,m), 3.65(3H,s), 5.0-5.1(2H,d),5.9-6.05(1H,m), 6.95-7.05(2H,d) and 7.3-7.4(1H,d); α²⁵ _(D) =+24.1°.

The methyl 4-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)butanoate usedas starting material was prepared in a similar manner to ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate (described inExample 1).

EXAMPLE 84

Using the method described in Example 83 but using(-)-3-ethynyl-3-hydroxyquinuclidine in place of(+)-3-ethynyl-3-hydroxyquinuclidine there was thus obtained (-)-3-2-(2-allyl-4-(3-methoxycarbonylpropyl)phenyl)ethynyl!quinuclidine-3-ol;NMR(CDCl₃): 1.4-1.5(1H,m), 1.55-1.8(1H,m), 1.8-2.2(5H,m), 2.1-2.4(2H,t),2.6-2.7(2H,t), 2.8-3.0(2H,m), 3.0-3.15(1H,d), 3.3-3.4(1H,d),3.4-3.6(2H,m), 3.66(3H,s), 5.0-5.1(2H,m), 5.9-6.1(1H,m),6.95-7.05(2H,m), 7.3-7.4(1H,d), α²⁵ _(D) =-20.3°.

EXAMPLE 85

Sodium hydroxide (44 mg) was added to a mixture of (+)-3-2-(2-allyl-4-(3-methoxycarbonylpropyl)phenyl)ethynyl!quinuclidin-3-ol,water (1 ml) and methanol (0.5 ml). The reaction mixture was stirred atambient temperature overnight. The reaction mixture was evaporated todryness. Water was added to the residue, and the mixture acidified usingdilute aqueous hydrochloric acid. The mixture was evaporated and acetonewas added to the residue. The mixture was filtered and the filtrateevaporated to give (+)-3-2-(2-allyl-4-(3-carboxypropyl)phenyl)ethynyl!quinuclidin-3-olhydrochloride as a gum (62 mg), NMR: 1.7-1.9(3H,m), 1.9-2.1(1H,m),2.1-2.3(4H,m), 2.5-2.65(2H,m), 3.1-3.6(4H,m), 5.0-5.15(2H,d),5.46(1H,m), 6.45(1H,t), 7.05-7.1(2H,m) and 7.3-7.4(1H,d); α²⁵ _(D) =-3.0

EXAMPLE 86

Using a similar method to that described in Example 1 but using(+)-3-ethynyl-3-hydroxyquinuclidine and methyl5-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)pentanoate as startingmaterials there was thus obtained (+)-3-2-(2-allyl-5-(4-methoxycarbonylbutyl)phenyl)ethynyl!quinuclidine-3-ol,NMR: 1.3-1.5(1H,m), 1.55-1.7(5H,m), 1.7-2.2(4H,m), 2.25-2.40(2H,m),2.55-2.7(2H,m), 2.7-3.0(4H,m), 3.0-3.1(1H,d), 3.25-3.4(1H,d),3.4-3.5(2H,m), 3.65(3H,s), 5.0-5.1(2H,m), 5.85-6.1(1H,m), 6.9-7.0(2H,m)and 7.3-7.4(1H,d); α²⁵ _(D) =+19.2°

EXAMPLE 87

A mixture of 3-2-(2-allyl-4-methoxycarbonylphenyl)ethynyl!quinuclidin-3-ol (0.64 g),sodium cyanide (50 mg) and N,N-dimethylethanolamine (10 ml) was heatedat 90° C. for 24 hours. The mixture was evaporated to give an oil whichwas partitioned between ethyl acetate and water. The organic phase wasseparated, washed with brine, dried (MgSO₄) and evaporated. The residuewas purified by flash column chromatography on silica gel using 10%methanol in dichloromethane containing 1% ammonia (density 0.88 g/cm³)as eluent to give 3-2-(2-allyl-4-(2-(N,N-dimethylamino)ethoxycarbonyl)phenyl)ethynyl!quinuclidin-3-olas a gum (0.559 g); microanalysis found: C, 66.7; H, 7.6; N, 6.7%, C₂₃H₃₀ N₂ O₃.0.4CH₂ Cl₂.0.1 H₂ O requires 7.47; N, 6.7%; NMR (CDCl₃):1.32-1.55(1H, m), 1.55-1.88(1H, m), 1.88-2.20(3H, m), 2.33(6H, s),2.70(2H, t), 2.65-3.15(4H, m), 3.07(1H, d), 3.33(1H, dd), 3.56(2H, d),4.41(2H, t), 4.98-5.15(2H, m), 5.29(CH₂ Cl₂), 5.85-6.10(1H, m), 7.43(1H,d) and 7.71-7.90(2H, m); m/Z 383 (M+H).

EXAMPLE 88

A methanolic solution of potassium hydroxide was added to a solution of3- 2-(2-allyl-4-methoxycarbonylphenyl)ethynyl!quinuclidin-3-ol (0.975 g)in methanol (10 ml) until hydrolysis was complete as judged thin layerchromatography. The precipitate formed was collected by filtration,washed with pentane and dried over phosphorus pentoxide. A mixture ofthe dried solid (0.45 g) and 2-chloro-N,N'-dimethylacetamide (0.144 ml)in 5 ml of 1,3-dimethyl-3,4,6-tetrahydro 2-pyrimidinone (DHPU) washeated at 70° C. for 3 hours. The mixture was cooled to ambienttemperature and partitioned between water and ethyl acetate. The organicphase was washed with brine and dried (MgSO₄). Evaporation gave an oilwhich was purified by chromatography on silica gel using a gradient of0% to 10% methanol in dichloromethane containing 1% ammonia (density0.88 g/cm³) as eluent to give 3-2-(2-allyl-4-(2--N,N'-dimethylacetamidoxy)carbonylphenyl)ethynyl!quinuclidin-3-ol as a gum (56 mg); microanalysis found:C, 67.4; H, 7.5; N, 7.1%; C₂₃ H₂₈ N₂ O₄ 0.75H₂ O requires: C, 67.4; H,7.25; N, 6.83%; NMR (CDCl₃): 1.35-1.55(1H, m), 1.55-1.80(1H, m),1.87-2.20(3H, m), 2.75-3.15(11H, m), 3.33(1H, dd), 3.56(2H, d), 4.94(2H,s), 4.98-5.15(2H m), 5.85-6.07(1H, m), 7.45(1H, d) and 7.80-8.00(2H, m);m/Z 397 (M+H).

EXAMPLE 89

A mixture of 3- 2-(2-ethoxy-4-formylphenyl)ethynyl!quinuclidin-3-ol (598mg), carbethoxymethylenetriphenylphosphorane (1.04 g) in toluene (10 ml)was heated at 100° C. for 5 hours. The reaction mixture was cooled toambient temperature and the toluene evaporated to give a solid which wascrystallised from acetonitrile to give 3-2-(2-ethoxy-4-(2-ethoxycarbonylethenyl)phenyl)ethynyl!quinuclidin-3-ol(328 mg) as a solid, m.p. 152-153° C.; microanalysis found: C, 71.5; H,7.3; N, 3.7%; C₂₂ H₂₇ NO₄ requires: C, 71.5: H, 7.37; N, 3.79%; NMR(CDCl₃): 1.33(3H, t), 1.36-1.52(4H, m), 1.55-1.70(1H, m), 1.90-2.30(4H,m), 2.73-3.00(4H, m), 3.04(1H, d), 3.34(1H, dd), 4.09(2H, q), 4.26(2H,q), 6.33-6.45(1H, d), 6.93-7.03(1H, d,), 7.03(1H, dd), 7.35(1H, d),7.60(1H, d); m/Z 370 (M+H).

The 3- 2-(2-ethoxy-4-formylphenyl)ethynyl!quinuclidine-3-ol used asstarting material was prepared as follows.

Ethyl-3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate wasprepared from ethyl vanillin using the procedure described in Example 1for the preparation of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate. Thus therewas obtained 3-ethoxy-4-trifluoromethylsulphonyloxybenzaldehyde as anoil; NMR (CDCl₃): 1.50(3H, t), 4.22(2H, q), 7.36-7.58(3H, m), 9.97(1H,s); m/Z 299 (M+H).

Using the method described in Example 1 but with3-ethoxy-4-trifluoromethylsulphonyloxybenzaldehyde in place of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate there was thusobtained 3- 2-(2-ethoxy-4-formylphenyl)ethynyl!quinuclidin-3-ol as asolid, m.p. 148-153° C.; microanalysis, found: C, 71.8; H, 7.3; N, 4.5%;C₁₈ H₂₁ NO₃ requires: C, 72.2; H, 7.07; N, 4.68%; NMR (CDCl₃):1.35-1.54(1H, m), 1.45(3H, t), 1.56-1.73(1H, m), 1.98-2.20(3H, m),2.85(4H, br t), 3.05(1H, d), 3.37(1H, dd), 4.13(2H, q), 7.30-7.40(2H,m), 7.50(1H, d), 9.93(1H, s); m/Z 300 (M+H).

EXAMPLE 90

The procedure described in Example 35 was repeated using(+)-3-ethynyl-3-hydroxyquinuclidine in place of (±)-3-ethynyl-3-hydroxyquinuclidine to give (+)-3-2-(2-allyl-4-(3-methoxypropyl)phenyl)ethynyl!quinuclidin-3-ol as an oil,NMR: 1.3-1.5 (1H, m), 1.6-1.8 (3H, m), 1.8-2.2 (3H, m), 2.53-2.65 (2H,t), 2.65-3.15 (6H, m), 3.2 (3H s), 3.25-3.35 (2H, t), 3.5-3.6 (2H, d),5.0-5.1 (2H, m), 5.6 (1H, s), 5.8-6.6 (1H, m), 7.0-7.1 (2H, d) and7.2-7.3 (2H, d). α!²⁰ _(D) +15.4°.

EXAMPLE 91

The procedure described in Example 35 was repeated using (-)3-ethynyl-3-hydroxyquinuclidine in place of (±)3-ethynyl-3-hydroxyquinuclindine to give (-)-3-2-(2-allyl-4-(3-methoxypropyl)phenyl)ethynyl!quinuclindin-3-ol as anoil, NMR: 1.3-1.5 (1H, m), 1.5-1.7 (1H, m), 1.7-1.85 (2H, m), 1.85-2.05(3H, m), 2.55-2.65 (2H, t), 2.65-2.8 (4H, m), 2.8-3.0 (1H, d) 3.05-3.15(1H, d), 3.2 (3H, s), 3.25-3.35 (2H, t), 3.4-3.5 (2H, d), 5.0-5.1 (2H,m), 5.6 (1H, s), 5.9-6.0 (1H, m), 7.0-7.1 (2H, d) and 7.2-7.3 (2H, d);α!²⁰ _(D) -19.4°.

EXAMPLE 92

Using the procedure described in Example 11, but with1-allyl-2-trifluoromethylsulphonyloxy-5-(2-methoxyethoxymethyl)benzenein place of 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane, there wasthus obtained 3-2-(2-allyl-4-(2-methoxyethoxymethyl)phenyl)ethynyl!quinuclidin-3-ol asan oil, NMR: 1.25-1.45 (1H, m), 1.5-1.7 (1H, m), 1.8-2.1 (3H, m),2.6-3.2 (6H, m), 3.3 (3H, s), 3.45-3.6 (6H, m), 4.5 (2H, s), 5.0-5.2(2H, m), 5.6 (1H, s), 5.9-6.1 (1H, m) and 7.1-7.4 (3H, m).

The compound of formula 2(2=trifluoromethysulphonyloxy) used as startingmaterial was prepared as follows.

2-(4-bromobenzyloxy) 1-methoxyethane (preparation described in Example11) (10 g) was added to a stirred mixture of oven dried magnesium (2.74g) in tetrahydrofuran (20 ml) under an atmosphere of argon. A crystal ofiodine was added and the mixture heated until an exothermic reactioncommenced. A solution of the remaining2-(4-bromobenzyloxy)-1-methoxyethane (13.4 g) in tetrahydrofuran (60 ml)was added dropwise to maintain the temperature of the reaction mixtureat reflux. When the addition was complete the mixture was heated atreflux for a further 20 minutes, allowed to cool and added totrimethylborate (11.74 g) in tetrahydrofuran (60 ml) under argon at -10°C., dropwise over 45 minutes whilst maintaining the temperature below-5° C. After stirring for 15 minutes, chilled acetic acid (9.36 g) wasadded, followed by the dropwise addition of 30% hydrogen peroxide (11.77ml) in water (11 ml) whilst maintaining the temperature below 0° C. Themixture was allowed to warm to ambient temperature over a period of 20minutes and then washed successively with saturated ammonium sulphatecontaining ferrous ammonium sulphate until the aqueous layer no longerturned brown. The organic layer was dried (MgSO₄) and evaporated. Theresidue was dissolved in ether (100 ml) and extracted into IM aqueoussodium hydroxide (50 ml×3). The aqueous extract was acidified with 2Maqueous hydrochloric acid and the mixture was extracted with ethylacetate (3×50 ml). The ethyl acetate extracts were combined, dried(MgSO₄) and evaporated. The residue was further purified by flashchromatography on silica gel using 10% ethyl acetate in toluene aseluent to give 2-(4-hydroxybenzyloxy)-1-methoxyethane (10.4 g) as acolourless oil; NMR (CDCl₃): 3.4 (3H, s), 3.5-3.7 (4H, m), 4.5 (2H, s),6.7-6.8 (2H, d), 7.1-7.3 (2H, d).

This material was used to prepare using an analogous procedure to thatdescribed in example 35 for the preparation of3-(-4-allyloxyphenyl)propanol. There was thus obtained2-(4-allyloxybenzyloxy)-1-methoxyethane as an oil. NMR (CDCl₃): 3.4 (3H,s), 3.5-3.7 (4H, m), 4.5-4.6 (4H, m), 5.2-5.5 (2H, m), 6.0-6.2 (1H, m),6.8-6.9 (2H, d), 7.2-7.3 (2H, d).

This material was used to prepare2-(2-allyl-4-hydroxybenzyloxy)-1-methoxyethane using an analogousprocedure to that described in example 35 for the preparation of3-(2-allyl-4-hydroxyphenyl)-1-methoxypropane. There was thus obtained2-(2-allyl-4-hydroxybenzyloxy)-1-methoxy ethane as a colourless oil, NMR(CDCl₃): 3.4 (5H, m), 3.5-3.7 (4H, m), 4.5(2H,s), 5.05-5.2 (3H, m)5.9-6.1 (1H, m), 6.7-6.8 (1H, d), 7.05-7.15 (2H, m).

This material was used to prepare2-(3-allyl-4-trifluoromethylsulphonyloxybenzyloxy)-1-methoxyethane usingan analogous procedure to that described in example 1 for thepreparation of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate. There wasthus obtained 2-(2-allyl-4-hydroxybenzyloxy)-1-methoxyethane as acolourless oil, NMR (CDCl₃) 3.4 (3H, s), 3.45-3.55 (2H, d), 3.55-3.7(4H, m), 4.6 (2H, s), 5.0-5.2 (2H, m), 5.8-6.0 (1H, m), 7.2-7.4 (3H, m).

EXAMPLE 93

A solution of hydrogen chloride in ethanol was added dropwise to astirred solution of 3-(4-cyanomethylphenoxymethyl)quinuclidin-3-olborane complex (0.3 g) in acetone (3 ml, analar) until the solution waspH1. A solid separated and the mixture was stirred for 2 hours atambient temperature under an atmosphere of argon. The solid wascollected by filtration and washed with acetone (3 ml) to give3-(4-cyanomethylphenoxymethyl)quinuclidin-3-ol hydrochloride (0.27 g) asa yellow solid, m.p. 185-188° C.; microanalysis, found: C, 61.7; H, 7.1;N, 8.7%; C₁₆ H₂₀ N₂ O₂ HCl 0.15 H₂ O requires: C, 61.7; H, 6.9; N, 9.0%;NMR: 1.55-2.05 (3H, m), 2.1-2.35 (2H, m), 2.95-3.5 (6H, m), 3.9-3.95(2H, s) 4.0-4.15 (2H, q), 5.45-5.7 (1H, s), 6.95-7.05 (2H, d), 7.25-7.35(2H, d) and 10.5-10.8 (1H, br), m/z 273 (M+H).

The 3-(4-cyanomethylphenoxymethyl)quinuclidin-3-ol borane complex usedas starting material was prepared as follows.

A mixture of 4-hydroxybenzyl cyanide (0.27 g), 3-methylenequinuclidineoxide borane complex (0.31 g), and anhydrous potassium carbonate (0.42g) in dry dimethylformamide (1 ml) was heated at 75° C. for 7 hoursunder an atmosphere of argon. There was thus obtained3-(4-cyanomethylphenyloxymethyl)quinuclidin-3-ol borane complex as anorange solid.

EXAMPLE 94

The procedure described in Example 93 was repeated using3-(4-styrylphenoxymethyl)quinuclidin-3-ol borane complex (0.25 g),instead of 3-(4-cyanomethylphenoxymethyl)quinuclidin-3-ol boranecomplex, in acetone (5 ml, analar). There was thus obtained3-(4-styrylphenoxymethyl)quinuclidin-3-ol hydrochloride (0.23 g) as acolourless solid, m.p. 235-238° C.; microanalysis, found: C, 70.2; H,7.1; N, 3.6%; C₂₂ H₂₅ NO₂ HCl 0.25 H₂ O requires: C, 70.2; H, 7.1; N,3.7%; NMR: 1.55-2.05 (3H, m), 2.1-2.35 (2H, m), 2.95-3.5 (6H, m),4.0-4.2 (2H, q), 5.3-5.85 (1H, br), 6.9-7.1 (2H, d), 7.1-7.2 (2H, d),7.2-7.3 (1H, m), 7.3-7.45 (2H, t) and 7.45-7.7 (4H, m), m/z 336 (M+H).

The 3-(4-styrylphenoxymethyl)quinuclidin-3-ol borane complex used asstarting material was prepared from 4-hydroxystilbene using an analagousprocedure to that described in Example 93 for the preparation of theborane starting material. The procedure described in Example 93 wasrepeated using 4-hydroxystilbene (0.39 g) instead of 4-hydroxybenzylcyanide, except that the reaction mixture was extracted with ethylacetate (50 ml). The ethyl acetate extract was washed with water (3×20ml), dried (Na₂ SO₄) and evaporated. There was thus obtained3-(4-styrylphenoxymethyl)quinuclidin-3-ol borane complex (0.28 g), as anoff-white solid.

EXAMPLE 95

The procedure described in Example 93 was repeated using 3-4-(2-cyanoethyl)phenoxymethyl!quinuclidin-3-ol borane complex (0.3 g),instead of 3-(4-cyanomethylphenoxymethyl)quinuclidin-3-ol boranecomplex, except that the reaction mixture was evaporated. The residualgum was dissolved in aqueous 1M aqueous hydrochloric acid (3 ml) and thesolution was washed with ethyl acetate (4×3 ml). The aqueous layer wasbasified with solid sodium carbonate and the mixture was extracted withethyl acetate (3×4 ml). The ethyl acetate extracts were combined, dried(Na₂ SO₄) and evaporated. The solid residue was triturated with diethylether to give 3- 4-(2-cyanoethyl)phenoxymethyl!quinuclidin-3-ol (0.15 g)as a colourless solid, m.p. 92-94° C.; microanalysis, found: C, 70.0; H,7.8; N, 9.5%; C₁₇ H₂₂ N₂ O₂ 0.3H₂ O requires: C, 70.0; H, 7.8; N, 9.6%;NMR (CDCl₃): 1.3-1.5 (1H, m), 1.5-1.7 (2H, m), 2.0-2.2 (2H, m), 2.3-2.6(1H, br), 2.55-2.65 (2H, t), 2.6-3.1 (8H, m), 3.8-4.1 (2H, q), 6.85-6.95(2H, d) and 7.1-7.2 (2H, d), m/z 287 (M+H).

The 3- 4-(2-cyanoethyl)phenoxymethyl!quinuclidin-3-ol borane complexused as starting material was prepared from3-(4-hydroxyphenyl)propionitrile using an analogous procedure to thatdescribed in Example 93 for the preparation of the borane startingmaterial. The procedure described in Example 93 was repeated using3-(4-hydroxyphenyl)propionitrile (0.29 g) instead of 4-hydroxybenzylcyanide. There was thus obtained 3-4-(2-cyanoethyl)phenoxymethyl!quinuclidin-3-ol borane complex (0.32 g)as an oil.

EXAMPLE 96

In a similar manner to that in Example 93,3-(2-allyl-4-hydroxymethylphenyloxymethyl)quinuclidin-3-ol boranecomplex (157 mg) was deprotected to give3-(2-allyl-4-hydroxymethylphenyloxymethyl)quinuclidin-3-ol hydrochloride(121 mg) which was obtained as a white crystalline solid hydrochloridedirectly from the reaction mixture on adding an equal volume of ether;microanalysis, found: C, 62.2; H, 7.7; N, 3.8%; C₁₈ H₂₅ NO₃hydrochloride hemihydrate requires, C, 62.0; H, 7.8; N, 4.01%; NMR:1.6-2.0 (3H, m), 2.3-2.4 (2H, bs), 2.9-3.7 (9H, m), 3.9-4.2 (2H, q), 4.4(2H, s), 4.95-5.15 (2H, m), 5.15-5.65 (1H, bs), 5.85-6.1 (1H, m) and6.85-7.2 (3H, m), m/z 304 (M+H).

The starting material was prepared as follows. In a manner similar toexample 51 but using a 15 hour reaction time, 2-allyl-4-formylphenol(1.0 g) was reacted with 3-methylenequinuclidine oxide (0.944 g) in DMF(3.1 ml) to afford 3-(2-allyl-4-formylphenyloxymethyl)quinuclidin-3-olborane complex (869 mg), obtained as a white crystalline solid afterpurification by chromatography on silica gel eluted with 15%acetone/pentane, NMR: 0.8-2.0 (6H, m), 2.0-2.3 (2H, bs), 2.65-3.1 (6H,m), 3.44-3.49 (2H, d), 4.14 (2H, s), 5.0-5.35 (3H, m), 5.87-6.11 (1H,m), 7.18-7.22 (1H, d), 7.68-7.69 (1H, d), 7.75-7.87 (1H, dd) and 9.86(1H, s).

A solution of 3-(2-allyl-4-formylphenyloxymethyl-3-hydroxyquinuclidineborane complex (175 mg) in gently warmed ethanol (2.0 ml) was treatedwith sodium borohydride (24 mg). After 1 hour the ethanol was removed byevaporation and the residue partitioned between ether (3×5 ml) and water(2 ml). The ether layers were combined washed with water (3 ml), dried(MgSO₄) and evaporated to give a colourless gum (176 mg) which waspurified by chromatography on silica gel eluted successively with 20%and then 30% acetone/pentane to afford3-(2-allyl-4-hydroxymethylphenyloxymethyl)quinuclidin-3-ol boranecomplex (169 mg) as a colourless gum.

EXAMPLE 97

Sodium borohydride (380 mg) was added to a solution of 3-2-(2-allyl-4-formylphenyl)ethynyl!quinuclidin-3-ol (2.95 g) in ethanol(50 ml) whilst maintaining the temperature at 5° C. The resultingmixture was stirred at 25° C. for 2 hours and the ethanol was thenevaporated. The residue was stirred with acetone (25 ml) and 1M aqueoushydrochloric acid (50 ml) was then added. The resulting mixture wasstirred at 25° C. for 1 hour and sodium hydrogen carbonate (4.5 g) wasthen added. The mixture was extracted with ethyl acetate (3×50 ml), theethyl acetate extracts combined, washed with brine (50 ml), dried (Na₂SO₄) and evaporated. The residue was dissolved in dichloromethane (85ml) and triethylamine (1.8 ml) was added. A solution of pivaloylchloride (1.14 g) in dichloromethane (8 ml) was added to the mixturewhilst maintaining the temperature at 5° C. The resulting mixture wasstirred at 25° C. for 12 hours. The dichloromethane was removed byevaporation and the residue was dissolved in ethyl acetate (215 ml). Themixture was washed with brine (100 ml), saturated sodium hydrogencarbonate solution (100 ml), dried (Na₂ SO₄) and evaporated to give aresidue which was purified by medium pressure column chromatography onalumina (Alumina N32-63) using a 49:1 (v/v) mixture of ethyl acetate andmethanol as eluent to give 3-2-(4-trimethylacetyloxymethyl-2-allylphenyl)ethynyl!quinuclidin-3-ol asa solid, m.p. 73° C.; microanalysis, found: C, 74.9; H, 8.2; N, 3.8%;C₂₄ H₃₁ NO₃ 0.2H₂ O requires: C, 74.9; H, 8.2; N, 3.6%; NMR (CDCl₃): 1.2(9H, s), 1.4 (1H, m), 1.65 (1H, m), 2.1 (3H, m), 2.3 (1H, m), 2.8 (4H,t), 3.1 (1H, d), 3.3 (1H, dd), 3.5 (2H, d), 5.1 (4H, m), 5.9 (1H, m),7.1 (2H, m) and 7.4 (1H, d), m/z 382 (M+H).

EXAMPLE 98

Sodium borohydride (380 mg) was added to a solution of 3-2-(4-formyl-2-allylphenyl)ethynyl!quinuclidine-3-ol (2.95 g) andmethylamine hydrochloride (1.01 g) in ethanol (50 ml) whilst maintainingthe temperature at 5° C. The resulting mixture was stirred at 25° C. for12 hours, filtered and the filtrate evaporated to leave a residue whichwas suspended in 1M aqueous sodium hydroxide solution (30 ml) andextracted with ethyl acetate (3×50 ml). The ethyl acetate extracts werecombined, washed with brine (50 ml), dried (Na₂ SO₄) and evaporated. Theresidue was triturated with diethyl ether to give 3-2-(4-methylaminomethyl-2-allylphenyl)ethynyl!quinuclidin-3-ol as asolid, m.p. 80° C.; microanalysis, found C, 75.1; H, 8.3; N, 8.6%; C₂₀H₂₆ N₂ O.0.5H₂ O requires: C, 75.2; H, 8.5; N, 8.8%; NMR (CDCl₃): 1.4(-1H, m), 1.65 (1H, m), 2.1 (5H, m), 2.5 (3H, s), 2.8 (4H, t), 3.1 (1H,d), 3.3 (1H, dd), 3.5 (2H, d), 3.7 (2H, s), 5.1 (4H, m), 5.9 (1H, m),7.1 (2H, m) and 7.4 (1H, d), m/z 311 (M+H).

The 3- 2-(4-formyl-2-allylphenyl)ethynyl!quinuclidine-3-ol used asstarting material was prepared using the method described in Example 1,but with 3-allyl-4-trifluoromethylsulphonyloxybenzaldehyde in place ofethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)-propionate. Therewas thus obtained 3- 2-(4-formyl-2-allylphenyl)ethynyl!quinuclidine-3-olas a solid, m.p. 132-133° C.; microanalysis, found: C, 76.5; H, 7.3; N,4.5% C₁₉ H₂₁ NO₂ 0.2 H₂ O requires C, 76.4; H, 7.2; N, 4.7%; NMR(CDCl₃): 1.4 (1H, m), 1.65 (1H, m), 2.1 (3H, m), 2.8 (4H, t), 3.1 (1H,d), 3.3 (1H, dd), 3.6 (2H, d), 5.1 (2H, m), 5.9 (1H, m), 7.3 (1H, d),7.5 (2H, m) and 10.0 (1H, s), m/z 296 (M+H).

The 3-allyl-4-trifluoromethylsulphonyloxybenzaldehyde was prepared usingthe method described in Example 1, but with 4-hydroxybenzaldehyde inplace of ethyl 3-(4-hydroxyphenyl)-propionate. There was thus obtained3-allyl-4-trifluoromethylsulphonyloxybenzaldehyde as an oil; NMR(CDCl₃): 3.6 (2H, d), 5.2 (2H, m), 6.0 (1H, m), 7.5 (1H, d), 7.9 (2H, m)and 10.0 (1H, s).

EXAMPLE 99

3- 2-(4-formyl-2-allylphenyl)ethynyl!quinuclidin-3-ol (1.0 g) andmethoxylamine hydrochloride were dissolved in ethanol (35 ml) and themixture stirred at 25° C. for 12 hours. The ethanol was evaporated andthe residue crystallised from ethyl acetate to give 3-2-(4-methoxyiminomethyl-2-allylphenyl)ethynyl!quinuclidin-3-olhydrochloride as a solid, m.p. 143° C.; microanalysis, found: C, 64.7;H, 7.0; N, 8.0% C₂₀ H₂₄ N₂ O₂ HCl. 0.5H₂ O requires C, 64.9; H, 7.0; N,7.6% NMR ( CD₃ !₂ SO/CD₃ COOD): 1.5-2.3 (5H, m), 3.2 (4H, t), 3.4 (1H,d), 3.6 (1H, dd), 3.9 (3H, s), 5.1 (2H, m), 6.0 (1H, m), 7.5 (3H, m) and8.2 (1H, s), m/z 325 (M+H).

EXAMPLE 100

Bis (triphenylphosphine)-palladium (II) chloride (147 mg) and copper (I)iodide (74 mg) were added to a solution of diethyl (3 allyl 4trifluoromethylsulphonyloxybenzylidine)malonate (3.3 g) and3-ethynylquinuclidine-3-ol (1.37 g) in dimethylformamide (17 ml) andtriethylamine (1.47 ml) at 5° C. under an atmosphere of argon. Themixture was stirred at 25° C. for 12 hours. Water (255 ml) was added andthe mixture extracted with ethyl acetate (3×100 ml). The ethyl acetateextracts were combined, washed with brine (100 ml), dried (Na₂ SO₄) andevaporated to give a residue which was purified by medium pressurecolumn chromatography on alumina (Alumina N32-63) using a 99.1 (v/v)mixture of ethyl acetate and methanol as eluent to give 3-2-(4-(2-dicarbethoxyethylenyl)-2-allylphenyl)ethynyl!quinuclidin-3-ol asa solid, m.p. 112° C., microanalysis, found: C, 71.1, H, 7.3; N, 3.1%;C₂₆ H₃₁ NO₅ requires C, 71.4; H, 7.1; N, 3.2%; NMR (CDCl₃): 1.3 (6H, t),1.4 (1H, m), 1.65 (1H, m), 2.1 (3H, m), 2.8 (4H, t), 3.1 (1H, d), 3.3(1H, dd), 3.5 (2H, d), 4.1 (4H, q), 5.1 (2H, m), 5.9 (1H, m), 7.1 (2H,m), 7.4 (1H, d) and 7.65 (1H, s), m/z 438 (M+H).

The diethyl (3-allyl-4-trifluoromethylsulphonyloxybenzylidine)malonateused as starting material was obtained as follows.

3-Allyl-4-hydroxybenzaldehyde (2.0 g) and diethylmalonate (2.37 g) weredissolved in toluene (50 ml) and piperidine (4 drops) and acetic acid(12 drops) were added. The mixture was heated at reflux using a Dean &Stark water separator until no more water was collected (2 hours). Thetoluene was evaporated to give a residue which was dissolved in diethylether (50 ml), washed with water (50 ml), saturated sodium hydrogencarbonate (25 ml), brine (25 ml), dried (MgSO₄) and evaporated to give aresidue which was purified by medium pressure column chromatography onsilica gel using a 4:1 (v/v) mixture of isohexane and ethyl acetate aseluent to give diethyl (3-allyl-4-hydroxybenzylidine)malonate as an oil,NMR (CDCl₃) 1.3 (6H, t), 3.4 (2H, d), 4.3 (4H, q), 5.2 (2H, m), 6.0 (1H,m), 6.6 (1H, d), 7.2 (2H, m) and 7.6 (1H, s).

Trifluoromethyl sulphonic anhydride (2.12 ml) was added dropwise over 20minutes to a stirred solution of diethyl(3-allyl-4-hydroxybenzylidine)malonate (3.7 g) in pyridine (12 ml) at 0°C. under an atmosphere of argon. The mixture was stirred at 0° C. for 16hours and was then added to cold water (180 ml). The aqueous mixture wasextracted with diethyl ether (3×100 ml), the diethyl ether extractscombined, washed with 1M aqueous hydrochloric acid (3×50 ml), brine (100ml), dried (MgSO₄) and evaporated to give a residue which was purifiedby medium pressure column chromatography on silica gel using a 19:1(v/v) mixture of isohexane and ethyl acetate as eluent to give diethyl(3-allyl-4-trifluoromethylsulphonyloxybenzylidine)malonate as an oil NMR(CDCl₃): 1.3 (6H, t), 3.5 (2H, d), 4.3 (4H, q), 5.2 (2H, m), 6.0 (1H,m), 7.3 (2H, m), 7.4 (1H, s) and 7.7 (1H, s).

EXAMPLE 101

A mixture of 3-2-(2-allyl-4-(butan-2-one)phenyl)ethynyl!quinuclidin-3-ol (0.3 g) inethanol (10 ml), sodium acetate (0.085 g) and 0-ethylhydroxylaminehydrochloride (0.1 g) was heated at reflux for 16 hours.

The mixture mixture was cooled and the solvent removed by evaporation.The residue was triturated with a 80:20:3 (v/v/v) mixture of ethylacetate/ethanol/triethylamine. The residue was purified by dry flashchromatography on 60H silica (Merck Art. No. 7736) using a 80:20:3(v/v/v) mixture of ethyl acetate/ethanol/triethylamine as eluent to give3- 2-(2-allyl-4-(3-ethoxyimino)butyl)ethynyl!quinuclidin-3-ol as an oil(0.22 g), microanalysis found; C, 73.5; H, 8.8; N, 7.2%; C₂₄ H₃₂ N₂O₂.3/4H₂ O requires C, 73.2; H, 8.6; N, 7.1%; m/z=381 (M+H).

EXAMPLE 102

Sodium borohydride (0.016 g) was added to a suspension of 3-2-(2-allyl-4-(butan-2-one)-phenyl)ethynyl!quinuclidin-3-ol (0.2 g), inethanol (5 ml) at 0° C. under an atmosphere of argon. The reactionmixture was allowed to warm to room temperature and stirred for 2 hours.

The reaction mixture was quenched by addition of saturated aqueousammonium chloride solution (10 ml) and water (10 ml). The aqueousmixture was extracted with ethyl acetate (3×15 ml). The ethyl acetateextracts were combined, dried (MgSO₄), and evaporated to give an oil,which was purified by flash chromatography on silica gel using a 80:20:3(v/v/v) mixture of ethyl acetate/ethanol/triethylamine as eluent to give3- 2-(2-allyl-4-(3-hydroxybutyl)phenyl)ethynyl!quinuclidin-3-ol as acolourless oil (0.155 g), microanalysis found: C, 73.3; H, 8.7; N, 3.6;C₂₂ H₂₉ NO₂.1.2M H₂ O requires C, 73.2; H, 8.8; N, 3.9; m/z=340 (M+H).

EXAMPLE 103

Using a similar procedure to that described in Example 11 but using3-(4-bromobenzyloxymethoxy)propane as starting material in place of1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane there was obtained 3-2-(4-(3-methoxypropoxy)methyl)phenyl)ethynyl!quinuclidin-3-ol as asolid, m.p. 121-122° C.; NMR: 1.2-1.4(1H, m), 1.5-1.65(1H, m),1.7-1.85(2H, q), 1.85-2.0(3H, m), 2.6-2.7(4H, t), 2.8-2.9(1H, d),3.0-3.1(1H, d), 3.2(3H, s), 3.35-3.45(2H, t), 3.45-3.55(2H, t), 4.45(2H,s), 5.5(1H, s) 7.25-7.35(2H, d) and 7.35-7.45(2H, d).

The starting material was prepared using an analogous procedure to thatdescribed in examples 11 for the preparation of1-(4-bromobenzyloxy-2-methoxyethane but starting from 3-methoxypropanol.There was thus obtained 3-(4-bromobenzyloxymethoxy)propane; NMR (CDCl₃):1.85-1.95(2H, q), 3.35(3H, s), 3.45-3.50(2H, t), 3.5-3.55(2H, t),4.5(2H, s), 7.2-7.3(2H, d) and 7.4-7.5(2H, d).

EXAMPLE 104

Using a similar procedure to that described in Example 11 but using2-(4-bromobenzyloxy)-1-(isopropoxy)ethane as starting material in placeof 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane there was obtained 3-2-(4-(2-isopropoxyethoxy)methyl)phenyl)ethynyl!quinuclidin-3-ol as asolid, m.p. 117-118° C.; NMR: 1.05-1.1(6H, d), 1.2-1.4(1H, m),1.5-1.7(1H, m), 1.8-2.0(3H, m), 2.6-2.75(4H, t), 2.8-2.9(1H, d),3.0(3.1(1H, d), 3.5-3.6(5H, m), 4.5(2H, s), 5.55(1H, s) and 7.25-7.4(4H,q).

The starting material was prepared using an analogous procedure to thatdescribed in Example 11 for the preparation of1-(4-bromobenzyloxy)-2-methoxyethane but starting from isopropoxyethanol. There was thus obtained2-(4-bromobenzyloxy)-1-(isopropoxy)ethane; NMR (CDCl₃): 1.1-1.2(6H, d),3.6(5H, m), 4.5(2H, s), 7.2-7.3(2H, d), and 7.4-7.5(2H, d).

EXAMPLE 105

Using a similar procedure to that described in Example 11 but using3-(4-bromophenyl)-1-(methoxy)propane as starting material in place of1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane there was obtained 3-2-(4-(3-methoxypropyl)phenyl)ethynyl!quinuclidin-3-ol as a solid, m.p.145° C.; NMR: 1.2-1.4(1H, m), 1.5-1.7(1H, m), 1.7-2.0(5H, m),2.55-2.75(6H, m), 2.75-2.9(1H, d), 3.0-3.15(1H, d), 3.2(3H, s),3.25-3.4(2H, m), 5.5(1H, s), 7.1-7.2(2H, d) and 7.25-7.74(2H, d).

The starting material was prepared using an analogous procedure to thatdescribed in Example 35 for the preparation of3-(4-allyloxyphenyl)-1-methoxypropane but starting from3-(4-bromophenyl)propyl bromide. There was thus obtained3-(4-bromophenyl)-1-(methoxy)propane; NMR (CDCl₃): 1.8-2.0(2H, m),2.6-2.7(2H, t), 3.3-3.4(5H, m), 7.0-7.1(2H, d) and 7.3-7.4(2H, d).

EXAMPLE 106

Using a similar procedure to that described in Example 11 but using3-(4-bromobenzyloxy)propane as starting material in place of1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane, there was obtained 3-2-(4-propoxymethylphenyl)ethynyl!quinuclidin-3-ol as a solid, m.p.140-141° C.; NMR (CDCl₃): 0.9-1.0(3H, t), 1.3-1.5(1H, m), 1.55-1.7(3H,m), 1.9-2.1(3H, m), 2.7-2.95(5H, m), 3.0-3.1(1H, d), 3.25-3.35(1H, d),3.4-3.5(2H, t), 4.5(2H, s), 7.2-7.3(2H, d) and 7.35-7.43(2H, d).

The starting material was prepared using an analogous procedure to thatdescribed in Example 11 for the preparation of1-(4-bromobenzyloxy)-2-methoxyethane but starting from n-propanol. Therewas thus obtained 3-(4-bromobenzyloxy)propane; NMR (CDCl₃): 0.9-1.0(3H,t), 1.6-1.7(2H, q), 3.4-3.5(2H, t), 4.5(2H, s), 7.15-7.3(2H, d) and7.4-7.5(2H, d).

EXAMPLE 107

Using a similar procedure to that described in Example 11 but with1-(4-bromo-2-fluorobenzyloxy)-2-methoxyethane in place of1-(4-bromobenzyloxy)-2-methoxyethane there was obtained 3-2-(4-(2-methoxyethoxymethyl!-2-fluorophenyl)ethynyl!quinuclidin-3-ol(13% yield) as a solid, m.p. 117-118° C.; microanalysis, found: C, 68.4;H, 7.5; N, 4.3%; C₁₉ H₂₄ FNO₃ requires: C, 68.4; H, 7.3; N, 4.2%; NMR:1.30(1H, m), 1.61(1H, m), 1.95(3H, m), 2.69(4H, t), 2.83(1H, d),3.07(1H, d), 3.25(3H, s), 3.49(2H, m), 3.56(2H, m), 4.52(2H, s),5.66(1H, s), 7.22(2H, m) and 7.39(1H, t); m/Z 333 (M+H).

The 1-(4-bromo-2-fluorobenzyloxy)-2-methoxyethane used as startingmaterial was obtained as follows.

2-Methoxyethanol (5.0 g) was added to a stirred suspension of sodiumhydride (2.64 g of a 60% mineral oil suspension) in DHF (200 ml) at roomtemperature and under a atmosphere of argon. The stirred mixture washeated to 60° C. and then cooled to 5° C. A solution of4-bromo-2-fluorobenzyl bromide (15 g) in dichlorobenzene (75 ml) wasadded over 15 minutes. The mixture stirred for 12 hours at roomtemperature, then for 1 hour at 60° C. and cooled. The mixture wasdiluted with iced water (600 ml) and extracted with ethyl acetate (3×200ml). The combined extracts were washed with 2M hydrochloric acid (100ml), water (2×100 ml), saturated brine (100 ml) and dried (MgSO₄).Evaporation of the solvents gave an oil which was distilled using ashort path distillation apparatus to give1-(4-bromo-2-fluorobenzyloxy)-2-methyoxyethane (11.6 g), furnacetemperature 125° C./0.01 bar; NMR (CDCl₃): 3.40(3H, s), 3.5-3.7(4H, m),4.58(2H, s) and 7.2-7.4(3H, m).

EXAMPLE 108

Sodium borohydride (1.14 g) was added portionwise over a period of 10minutes to a solution of 3--2-(2-formyl-4-ethoxycarbonylethylphenyl)ethynyl!quinuclidin-3-ol (2 g)and saturated aqueous sodium bicarbonate (2 ml) in methanol (10 ml) at10° C. under an atmosphere of argon. The reaction mixture was stirred atambient temperature 2 hours. An equal volume of water was added and themixture was extracted with ethyl acetate. The ethyl acetate extract wasdried (MgSO₄), evaporated and the residue was purified by chromatographyon silica gel (Varian Bond Elut S1 silica gel) using a gradient of 0 to20% ethyl acetate in hexane to give 3-2-{2-hydroxymethyl-4-ethoxycarbonylethylphenyl}-ethynyl!quinuclidin-3-olborane complex (480 mg) as a solid; NMR: 2.65(2H, t), 2.95(6H, m),3.2(1H, d), 3.3(1H, s), 3.4(1H, d), 3.65(1H, s), 4.73(2H, s), 7.1(1H,m), 7.28(1H, s), 7.35(1H, d); m/Z 358 (M+H).

EXAMPLE 109

Using the method described in Example 70, but with4-(2-iodophenoxy)-2-methylbut-2-ene (855 mg) in place of2-iodophenylacetonitrile and (+) 3-ethynyl-3-hydroxyquinuclidine inplace of 3-ethynyl-3-hydroxyquinuclidine there was thus obtained 3-2-{2-(3-methylbutox-2-ene)phenyl}ethynyl!quinuclidin-3-ol (427 mg) as asolid, m.p 175.1° C., microanalysis, found: C, 76.4; H, 8.3; N, 4.7%;C₂₀ H₂₅ NO₂ 0.15H₂ O requires: C, 76.5; H, 8.12; N, 4.46%; NMR 1.31(1H,m), 1.55(1H, m), 1.74(6H, d), 1.81-2.14(3H, m), 2.67(4H, t), 2.81(1H,d), 3.08(1H, d), 4.57(2H, d), 5.37-5.55(2H, m), 6.9(1H, t), 7.03(1H, d)and 7.29(2H, m); m/Z 312 (M+H).

EXAMPLE 110

Using the method described in Example 1, but carrying out the reactionat ambient temperature overnight and with2,2-dichloroethyl-2-iodobenzoate generated in situe by the reaction of2-iodobenzoyl chloride (718 mg) with 2,2-dichloroethanol (0.34 ml) intriethylamine (1 ml) as solvent at ambient temperature! in place ofethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate therewas thus obtained 3-2-{2-(2',2'-dichloroethoxycarbonyl)phenyl}ethynyl!quinuclidin-3-ol as asolid (396 mg), m.p. 160.7° C.; microanalysis, found: C, 57.9: H, 5.3;N, 4.1%; C₁₈ H₁₉ Cl₂ NO₃ 0.25H₂ O requires C, 58.0; H, 5.27; N, 3.76%;NMR: 1.31(1H, m), 1.6(1H, m), 1.98(3H, m), 2.6-3.05(6H, m), 4.72(2H, d),5.58(1H, s), 6.6(1H, t), 7.45-7.68(3H, m), 7.92(1H, d); m/Z 368° C.

EXAMPLE 111

Using the method described in Example 1, but carrying out the reactionat ambient temperature overnight and with 2-chloroethanol-2-iodobenzategenerated in situ by the reaction of 2-iodobenzoyl chloride (718 mg)with 2-chloroethanol (0.34 ml) in triethylamine (1 ml) as solvent atambient temperature)! in place of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate there was thusobtained 3- 2-{2-(2-chloroethoxycarbonyl)phenyl}ethynyl!quinuclidin-3-olas a solid (286 mg), m.p. 132.2° C.; microanalysis, found C, 63.8; H,6.1; N, 4.5%; C₁₈ H₂₀ ClNO₃, 0.25H₂ O requires C, 63.9; H, 6.11; N,4.14%; NMR: 1.32(1H, m), 1.57(1H, m), 1.94(3H, m), 2.7(4H, m),3.05-3.4(2H, m), 3.95(2H, m), 4.51(2H, m), 5.56(1H, s), 7.44-7.65(3H,m), 7.88(1H, d); m/Z 334 (M+H).

EXAMPLE 112

Using the method described in Example 1, but carrying out the reactionat ambient temperature overnight and with phenyl-2-iodobenzoate,generated in situ by the reaction of 2-iodo benzoyl chloride (678 mg)with phenol (279 mg) in triethylamine (1 ml) as solvent at ambienttemperature)! in place of ethyl3-(3-allyl-4-trifluoromethylsulphonoxyphenyl)propionate there was thusobtained 3- 2-{2-(phenoxycarbonyl)phenyl}ethynyl!quinuclidin-3-ol as asolid (472.5 mg), m.p. 60.3° C., microanalysis, found: C, 71.4; H, 5.8;N, 3.9; I, 2.8%; C₂₂ H₂₁ NO₃ 0.75H₂ O.0.07 HI requires C, 71.4; H, 61.5;N, 3.79; I, 2.4%; NMR: 1.3(1H, m), 1.5(1H, m), 1.9(3H, m), 2.67(4H, t),2.95(1H, +H₂ O), 3.14(1H, d), 5.15(1H, s), 7.25-7.7(8H, m), 8.03(1H, d);m/Z 348 (M+H).

EXAMPLE 113

Using the method described in Example 1, but carrying out the reactionat ambient temperature overnight and with2,2,2-trichloroethyl-2-iodobenzoate generated in situe by the reactionof 2-iodo benzoyl chloride (718 mg) with 2,2,2-trichloroethanol (0.34ml) in triethylamine (1 ml) as solvent at ambient temperature) in placeof ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate therewas thus obtained 3-2-{2-(2,2,2trichloroethoxycarbonyl)phenyl}ethynyl!quinuclidin-3-ol as asolid (533 mg), m.p. 127.4° C.; microanalysis, found C, 53.4; H, 4.6; N,3.4%; C₁₈ H₁₈ Cl₃ NO₃ requires C, 53.7; H, 4.51; N, 3.48%; NMR: 1.3(1H,m), 1.53(1H, m), 1.95(3H, m), 2.68(4H, t), 2.82(1H, d), 3.13(1H, d),5.14(2H, s), 5.57(1H, s), 7.5-7.7(3H, m), 7.98(1H, d); m/Z 404 (M+H).

EXAMPLE 114

A mixture of3-{2-(2-hydroxymethyl-4-ethoxycarbonylethylphenyl}ethynyl!quinuclidin-3-olborane complex (400 mg), triphenylphosphine (524 mg) and toluene (50 ml)was stirred at 0° C. under an atmosphere of argon. A solution ofdiethylazodicarboxylate (340 mg) in toluene (10 ml) was added over aperiod of 5 minutes and the reaction mixture stirred at ambienttemperature overnight. Water (50 ml) was added and the mixture extractedwith ethyl acetate. The ethyl acetate extracts were dried (MgSO₄) andevaporated. The residue was purified by chromatography on silica gel(Varian Band Elut S1 silca gel) using a gradient of 0 to 20% ethylacetate in hexane to give the product as a borane complex. Treatment at10° C. with hydrochloric acid dissolved in a mixture of acetone andethanol gave, upon evaporation, 3-2-{2-phenoxymethyl-4-ethoxycarbonylethylphenyl}ethynyl!quinuclidin-3-olas a gum; NMR (CDCl₃): 1.24(3H, t), 2.6(2H, t), 2.96(2H, t), 4.1(2H, q),5.08(H, s), 6.9-7.05(4H, m), 7.15-7.45(5H, m); m/Z 434 (M+H).

EXAMPLE 115

In a similar manner to that described in Example 1 but using3-ethynyl-3-hydroxyquinuclidine and methyl6-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)caproate as startingmaterials, there was thus obtained 3-2-(2-allyl-4-(5-methoxycarbonylpentyl) phenyl)ethynyl!quinuclidin-3-olas a gum (87 mg), NMR: 1.25-1.5(1H,m), 1.5-1.9(1H+H₂ O,m),1.9-2.1(1H,m), 2.2-2.3(2H,t), 2.5-2.6(2H,m), 2.7-3.0(4H,m),3.0-3.1(1H,d), 3.3-3.4(1H,dd), 3.45-3.55(2H,d), 3.65(3H,s),5.0-5.1(2H,m), 5.9-6.1(1H,m), 6.95-7.0(2H,m) and 7.3-7.35(1H,d), m/z396(M+H).

The methyl 6-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)caproate usedas starting material was prepared in a similar manner to ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate (described inExample 1).

EXAMPLE 116

In a similar manner to that described in Example 1 but using3-allyl-4-trifluoromethylsulphonyloxyphenylpropionate as startingmaterial there was thus obtained 3-2-allyl-3(4-propionitrile)ethynyl!quinuclidin-3-ol as a solid (478 mg),m.p. 124.3° C.; NMR (CDCl₃): 1.3-1.45(1H,m), 1.5-1.65(1H,m),1.8-2.1(3H,m), 2.5-2.6(2H,t), 2.7-2.9(5H,m), 2.9-3.05(1H,d),3.2-3.3(1H,dd), 3.4-3.5(2H,d), 4.95-5.1(2H,m), 5.8-6.0(1H,m), 6.9-7.0,(2H,m), and 7.3-7.35(1H,d), m/z 321(M+H).

The 3-allyl-4-trifluoromethylsulphonyloxyphenylproprionitrile used asstarting material was prepared in a similar manner to ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionte described inExample 1.

EXAMPLE 117

A solution of 3-2-{2-allyl-4-(2-ethoxycarbonylethyl)phenyl}ethynyl!quinuclidin-3-ol (1.0g) in methanol saturated with ammonia was allowed to stand at ambienttemperature for 48 hours. The solvent was evaporated to give an oilwhich, on trituration with diethyl ether, gave a solid. The solid wascrystallised from ethyl acetate to give 3-2-{2-allyl-4-(2-amidoethyl)phenyl}ethynyl!quinuclidin-3-ol as a solid(562 mg), m.p. 137.5° C.; microanalysis, found: C, 72.6; H, 7.70; N,7.80%, C₂₁ H₂₆ N₂ O₂. 0.5 H₂ O requires: C, 72.6; H, 7.77; N, 8.00%;NMR: 1.28-1.45(1H,m), 1.50-1.85(1H,m), 1.85-2.12(3H,m), 2.30(2H,t),2.75(10H,m), 5.05(2H,m), 5.60(1H,bs), 5.88-6.05(1H,m), 6.70(1H,bs),7.03(2H,m) and 7.25(2H, d and bs), m/z 339(M+H).

EXAMPLE 118

The procedure described in Example 117 was repeated using methanolicmethylamine in place of methanolic ammonia. There was thus obtained,after crystallisation from ethyl acetate, 3-2-{2-allyl-4-(2-methylamidoethyl)phenyl}ethynyl!quinuclidin-3-ol as asolid, m.p. 115.2° C.; microanalysis, found: C, 72.1; H, 8.30; N, 7.80%,C₂₂ H₂₈ N₂ O. 0.75H₂ O requires: C,72.2; H, 7.66; N, 7.66%; NMR( CD₃ !₂SO/CD₃ COOD): 1.62-1.82(1H,m), 1.92-2.10(1H,m), 2.10-2.30(3H,m),2.38(2H,t), 2.60(3H,s), 2.82(2H,t), 3.00-3.47(6H,m), 3.50(2H,d),5.05(2H,m), 5.90-6.05(1H,m), 7.05(2H,m) and 7.30(1H,d), m/z 353(M+H).

EXAMPLE 119

A solution of 3-2-{2-allyl-4-(2-ethoxycarbonylethyl)phenyl}ethynyl!quinuclidin-3-ol (734mg) in tetrahydrofuran (15 ml) was added over a period of 0.25 hours toa stirred suspension of lithium borohydride (450 mg) in tetrahydrofuran(15 ml) at 0° C. under an atmosphere of argon. The mixture was stirredfor 16 hours at ambient temperature. The tetrahydrofuran was removed byevaporation. Acetone (20 ml) was added slowly with stirring followed by1M aqueous hydrochloric acid (20 ml). The mixture was stirred for 1 hourat ambient temperature. The acetone was removed by evaporation and theaqueous mixture was basified to pH 12 using 2M aqueous sodium hydroxidesolution and then extracted with ethyl acetate (2×50 ml). The ethylacetate extracts were combined, washed with brine (2×30 ml), dried(MgSO₄) and evaporated. The residue was purified by flash columnchromatography on Meutral Alumina (ICN Alumma N 32-63) using a 9:1 (v/v)mixture of ethyl acetate and methanol as eluent to give 3-2-(2-allyl-4-(3-hydroxypropane)phenyl)ethynyl!quinuclidin-3-ol (123 mg)as a glass; NMR(CDCl₃): 1.35-1.52(1H,m), 1.58-1.73(1H,m), 1.87(2H,m),1.92-2.22(3H,m), 2.68(2H,t), 2.77-2.98(4H,m), 3.08(1H,d), 3.32(1H,d.d),3.50(2H,d), 3.63(2H,t), 4.98-5.12(2H,m), 5.85-6.08(1H,m), 7.01(2H,m) and7.33(1H,d): m/z 326(M+H).

EXAMPLE 120

Using the method described in Example 67 but using 3-2-(2-allyl-4-(2-methoxycarbonylpropyl)phenyl)ethynyl!quinuclidin-3-ol inplace of 3- 22-allyl-4-(2-ethoxycarbonylethyl)phenyl!ethynyl!quinuclidin-3-ol, therewas obtained 3- 2-2-allyl-4-(2-carboxypropyl)phenyl!ethynyl!quinuclidin-3-ol hydrochloridesalt as a solid, m.p. 45-47° C. (dec), NMR( CD₃ !₂ SO/CD₃ COOD):1.10(3H,d), 1.75-1.90(1H,m), 1.95-2.10(1H,m), 2.13-2.41(3H,m),2.62(2H,m), 2.93(1H,q), 3.15-3.33(4H,m), 3.40(1H,d), 3.51(2H,d),3.60(1H,d), 4.98-5.10(2H,m), 5.88-6.08(1H,m), 7.08(2H,m) and 7.37(1H,d),m/z 354(M+H).

EXAMPLE 121

Cuprous Iodide (150 mg) and tris-(dibenzylidene acetone)dipalladium (100mg) (100 mg) were added to a solution of3-((E)-2-tributylstannyl-1-ethenyl)-3-hydroxyquinuclidine (882 mg), andN-(1-butyl)-4-iodophenylacetamide (951 mg) in DMF (10 ml) under anatmosphere of argon. The reaction mixture was stirred at ambienttemperature for 15 minutes. The solvent was removed by evaporation, andthe residue was purifed by chromatography on silica gel using 20%methanol in dichloromethane containing 1% ammonia as eluent to give 3-(E)-2- 4- N-(1-butyl)-carboxamidomethyl!phenyl!vinyl!quinuclidin-3-ol,as a solid which was recrystallised from ethyl acetate to give a solid(330 mg), mpt: 128-130° C.; microanalysis, found: C:71.6; H: 8.6;N:7.7%; C₂₁ H₃₀ N₂ O₂ +0.15 CH₃ CO₂ C₂ H₅ +0.10 H₂ O requires: C: 72.0;H: 8.6; N:7.7%; 7.8%; NMR: 0.93-0.90, (3H,t), 1.15-1.55,(6H,m),1.57-1.75(2H,m), 1.93-2.10(H.bm), 2.55-2.82(5H,m), 2.85-2.90(1H,dd),3.00-3.08(2H,q), 3.35(2H,s), 4.72(1H,s), 6.50-6.63(2H,AB),7.18-7.38(4H,AB) and 7.90(H,bt); m/z343(M+H).

The N-(1-butyl)-4-iodophenylacetamide used as starting material wasprepared as follows.

1-Butylamine (1.83 g) was added to a solution of 4-iodophenylacetylchloride (2.80 g) in ether (25 ml), and the reaction mixture was stirredat ambient temperature for 5 minutes. The reaction mixture was thenpartitioned between water (30 ml) and ethyl acetate (50 ml). The organiclayer was washed with 2M aqueous hydrochloric acid (25 ml), water (30ml), brine (25 ml), dried (MgSO₄), and evaporated to give N-1-butyl,(4-iodophenyl)acetamide, as a colourless crystalline solid, (2.9 g),mp.: 100-102° C., NMR: 0.82-0.88(3H,t), 1.18-1.43(4H,m),3.00-3.06(2H,q), 3.35(2H,s), 7.03-7.67(4H,AB), 7.97(H,bt); m/z 318(M+H).

EXAMPLE 122

In a similar manner to Example 121, but using 4-iodophenylacetamide inplace of N-(1-butyl)-4-iodophenylacetamide, there was obtained 3-(E)-2-(4-carboxamidomethylphenyl)vinyl!quinuclidin-3-ol as a solid, m.p.180-184° C., (after recrystallisation from a mixture of ethylacetate/hexane), microanalysis, Found: C, 69.7; H: 8.1; N, 9.5%; C₁₇ H₂₂N₂ O₂ 0.5 H₂ O requires: C, 69.3; H:7.8; N:9.5% m/z 287 (M+H); NMR:1.17-1.53(2H,m), 1.60-1.75(2H,m), 1.92-2.08(H,m), 2.55-2.82(5H,m),2.85-2.90(1H,d), 3.33(2H,s), 4.72(H,s), 6.50-6.63(2H,AB) and 6.82(H,b).

The 4-iodophenylacetamide used as starting material was obtained asfollows.

Thionyl chloride (39.53) and DMF (2 drops) were added to a solution of4-iodophenylacetic acid (26.2 g), in dichloromethane (150 ml). Thereaction mixture was stirred at ambient temperature for 18 hours and thesolvent removed by evaporation to give 4-iodophenylacetyl chloride as anoil (23 g) which was purified by vacuum distillation; b.p. 118-119° C.(0.35 mmMg)

Concentrated aqueous ammonia (density, 0.88 g/cm³) was added to asolution of 4-iodophenylacetyl chloride (2.80 g) in ether (30 ml) andthe mixture was stirred at ambient temperature for 15 minutes. Theproduct, 4-iodophenylacetamide, was obtained as a colourless crystallinesolid (2.36 g), m.p: 200-204° C.; NMR: 3.34(2H,s), 6.87(H,bs),7.44(2H,bs), 7.04-7.68(4H,AB); m/z 262(M+H).

EXAMPLE 123

In a similar manner to Example 121, but using methyl(4-iodophenyl)acetate in place of N-(1-butyl)-4-iodophenylacetamide,there was obtained 3-(E)-2-(4-methoxycarbonylmethylphenyl)vinyl!quinuclidin-3-ol as a solid(135 mg), mp 133-136° C. (after recrystallisation from ethyl acetate),NMR: 1.12-1.55(2H,m), 1.67(2H,m), 2.00(H,bm), 2.58-2.90(6H,m),3.30(2H,s), 3.60(H,s), 3.64(2H,s), 4.73(H,s), 6.57(2H,s),7.17-7.40(4H,AB).

The methyl 4-iodophenylacetate used as starting material was prepared asfollows.

4-iodophenylacetyl chloride (2.80 g) was added to methanol (10 ml) andthe mixture stirred at ambient temperature for 15 minutes. The solventwas removed by evaporation to give methyl 4-iodophenylacetate as a redoil (2.73 g) which was used without further purification; NMR:3.62(s,3H), 3.67(s,2H), 7.05-7.70(AB,4H). m/z277(M+H)

EXAMPLE 124

The procedure used in Example 93 was repeated using 3-4-(3-hydroxypropyl)phenoxymethyl!quinuclidin-3-ol borane complex (0.24g) instead of 3-(4-cyanomethylphenoxymethyl)quinuclidin-3-ol boranecomplex, except that the reaction mixture was diluted with an equalvolume of diethyl ether and stirred for 16 hours to give 3-4-(3-hydroxypropyl)phenoxymethyl!quinuclidin-3-ol hydrochloride (0.17 g)as a colourless solid, m.p. 143-146° C.; microanalysis, found: C, 62.4;H, 8.0; N, 4.4%; C₁₇ H₂₅ NO₃ HCl requires: C, 62.3; H, 8.0; N, 4.3%;NMR: 1.5-2.0(5H,m), 2.1-2.3(2H,m), 2.4-2.6(2H,t), 2.9-3.4(6H, m),3.35-3.5(2H,t), 3.9-4.1(2H,s), 4.2-4.6(1H,br), 5.4-5.6(1H,s),6.8-6.95(2H,d), 7.05-7.2(2H,d)and 10.4-10.8(1H,s); m/z 292 (M+H).

The 3- 4-(3-hydroxypropyl)phenoxymethyl!quinuclidin-3-ol borane complexused as starting material was prepared from3-(4-hydroxyphenyl)-1-propanol using an analogous procedure to thatdescribed in Example 93 for the preparation of the borane startingmaterial. Thus, the procedure described in Example 93 was repeated using3-(4-hydroxyphenyl)-1-propanol (0.30 g) instead of 4-hydroxybenzylcyanide. There was thus obtained 3-4-(3-hydroxypropyl)phenoxymethyl!quinuclidin-3-ol borane complex (0.25g) as a solid.

EXAMPLE 125

Using the method described in Example 1, but with methyl3-(3-allyl-4-trifluromethylsulphonyloxyphenyl)-2,2-dimethylpropionate inplace of ethyl 3-(3-allyl-4-trifluromethylsulphonyloxyphenyl)propionate, there was thus obtained 3-2-(2-allyl-4-(2-methoxycarbonyl-2,2-dimethylethyl)phenyl)ethynyl!quinuclidin-3-olas an oil; NMR (CDCl₃): 1.15(6H,s), 1.32-1.50(1H,m), 1.57-1.77(1H,m),1.90-2.10(3H,m), 2.30(1H,m), 2.70-3.00(6H,m), 3.05(1H,d), 3.31(1H,dd),3.50(2H,d), 3.62(3H,s), 4.97-5.12(2H,m), 5.88-6.03(1H,m), 6.90(2H,m) and7.30(1H,d); m/z 482(M+H).

The methyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)-2,2-dimethylpropionateused as starting material was obtained as follows.

Allyl bromide (0.66 ml) was added to a stirred suspension of methyl2,2-dimethyl-3-(4-hydroxyphenyl)propionate (1.41 g) and potassiumcarbonate (1.08 g) in butan-2-one (12 ml). The reaction mixture washeated at reflux for 19 hours, cooled, and filtered. The filtrate wasevaporated to give methyl 2,2-dimethyl-3-(4-allyloxyphenyl)propionate(1.59 g) as an oil; NMR(CDCl₃): 1.17(6H,s), 2.78(2H,s), 3.65(3H,s),4.50(2H,m), 5.33(2H,m), 6.02(1H,m), 6.70(2H,m) and 7.00(2H,m); m/z248(M+).

A solution of methyl 2,2-dimethyl-3-(4-allyloxyphenyl)propionate (1.56g) in diphenyl ether was heated at reflux for 15 minutes. The reactionmixture was cooled to ambient temperature and the reaction mixture wasfiltered through a silica gel pad. Elution with a 4:1 (v/v) mixture ofhexane and ethyl acetate gave methyl2,2-dimethyl-3-(3-allyl-4-hydroxyphenyl)propionate (1.53 g) as a yellowoil; microanalysis, found: C, 72.2; H, 7.80%; C₁₅ H₂₀ O₃ requires: C,72.6; H, 8.12%; NMR(CDCl₃): 1.15(6H,s), 2.73(2H,s), 3.35(2H,m),3.63(3H,s), 4.87(1H,s), 5.10(2H,m), 5.95(1H,m), 6.67(1H,m) and6.83(2H,m); m/z 249 (M+H).

Trifluoromethane sulphonic anhydride (1.25 ml) was added to a stirredsolution of methyl 2,2-dimethyl-3-(3-allyl-4-hydroxyphenyl)propionate(1.51 g) in pyridine (6.0 ml) at 0° under an atmosphere of argon. After16 hours 1M hydrochloric acid (100 ml) was added to the reaction mixtureand the mixture was extracted with ether. The ether phase was washedwith brine, dried and evaporated to give an oil. Purification of the oilby chromatography on silica gel using a 9:1 (v/v) mixture ofhexane/ethyl acetate mixture as eluent give methyl2,2-dimethyl-3-(3-allyl-4-trifluoromethylsulphonyloxy)phenyl)propionate(2.18 g) as an oil; NMR(CDCl₃) 1.18(6H,s), 2.82(2H,s), 3.42(2H,d),3.63(3H,s), 5.10(2H,m), 5.92(1H,m), 7.02(2H,m) and 7.13(1H,d).

EXAMPLE 126

Using the method described in Example 1, but with methoxyethyl2-methyl-3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate inplace of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionateand (-)-3-ethynyl-3-hydroxy-quinuclidine in place of(±)-3-ethynyl-3-hydroxyquinuclidine there was thus obtained (-) 3-2-(2-allyl-4-methoxyethoxycarbonyl-1-methylethylphenyl)ethynyl!quinculidin-3-ol(as a diastereoisomic pair) as a yellow oil; microanalysis, found: C,71.0; H, 8.20; N, 3.10%; C₂₅ H₃₃ NO₄. 0.5 H₂ O requires C, 71.3; H,8.10; N, 3.30%; NMR(CDCl₃) 1.13(3H,d), 1.41(1H,m), 1.64(1H,m),2.06(3H,m), 2.75(8H,m), 3.30(4H,m), 3.52(4H,m), 4.18(2H,m), 5.06(2H,m),5.94(1H,m), 6.98(2H,m) and 7.31(1H,d); m/z 412(M+H).

The methoxyethyl2-methyl-3-(3-allyl-4-trifluromethylsulphonyloxyphenyl)propionate usedas starting material was prepared as follows.

Concentrated sulphuric acid (0.2 ml) was added to a stirred suspensionof 4-oxypropionyl-2-methylcinnamic acid (2.78 g) in 2-methoxyethanol (20ml) and the reaction mixture was heated at 100° C. for 16 hours. The2-methoxyethanol was removed by evaporation and saturated sodiumbicarbonate solution (20 ml) was added. The mixture was extracted withether. The ether phase was dried (MgSO₄) and evaporated to givemethoxyethyl 3-(4-hydroxyphenyl)-2-methyl cinnamate (2.60 g) as acolourless solid m.p.101.8° C.; NMR(CDCl₃): 2.12(3H,d), 3.44(3H,s),3.72(2H,t), 4.38(2H,t), 5.82(1H,m), 6.82(2H,m), 7.28(2H,d) and7.6(1H,s).

A solution of methoxyethyl 2-methyl 4-hydroxycinnamate (2.56 g) in ethylacetate (75 ml) was hydrogenated at atmospheric pressure and ambienttemperature over a 10% Pd-C catalyst (180 mg). The catalyst was removedby filtration and the filtrate was evaporated to give methoxyethyl2-methyl-3-(4-hydroxyphenyl)propionate (2.56 g) as an oil; NMR(CDCl₃):1.17(3H,d), 2.70(2H,m), 2.92(1H,q), 3.36(3H,s), 3.55(2H,m), 4.21(2H,m),5.16(1H,bs), 6.72(2H,m) and 7.01(2H,m).

Methoxyethyl 2-methyl-3-(4-allyloxyphenyl)propionate was prepared usingthe procedure used to prepare ethyl 3-(4-allyloxyphenyl)propionate (seeExample 1). Methoxyethyl 2-methyl-3-(3-allyl-4-hydroxyphenyl)propionatewas prepared from methoxyethyl 2-methyl-3-(4-allyloxyphenyl)propionateusing the method described in Example 1 for the preparation of ethyl3-(3-allyl-4-hydroxyphenyl)propionate. The product was isolated as ayellow oil; microanalysis; found: C, 69.0 H, 7.70%; C₁₆ H₂₂ O₄ requiresC, 69.0 H. 7.97%; m/z 279 (M+H).

The method described in Example 1 for the preparation of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate was used toconvert methoxyethyl 2-methyl-3-(3-allyl-4-hydroxyphenyl)propionate tomethoxyethyl2-methyl-3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate;NMR(CDCl₃): 1.18(3H,d), 2.73(2H,m), 3.00(1H,q), 3.36(3H,s), 3.42(2H,d),3.51(2H,m), 4.18(2H,m), 5.09(2H,m), 5.90(1H,m) and 7.13(3H,m); m/z 411(M+H).

EXAMPLE 127

Using the method described in Example 1 but using (+)3-ethynyl-3-hydroxy quinuclidine in place of (±)₃ -ethynyl-3-hydroxyquinuclidine and methoxyethyl 2-methyl-3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate in place of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate there was thusobtained (as a diastereomeric pair) (+) 3- 2-(2-allyl-4-methoxyethoxycarbonyl-1-methylethylphenyl)ethynyl!quinuclidin-3-ol as an oil;NMR(CDCl₃): 1.16(3H,d), 1.44(1H,m), 1.64(1H,m), 2.05(3H,m), 2.87(8H,m),3.38(4H,m), 3.52(4H,m), 4.18(2H,m), 5.05(2H,m), 5.94(1H,m), 6.98(2H,m)and 7.31(1H,d); m/z 412 (M+H).

EXAMPLE 128

Using the method described in Example 1 but using ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)-1-methyl propionate inplace of ethyl3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate, there wasthus obtained 3-2-(2-allyl-4-(2-ethoxycarbonyl-1-methylethyl)phenyl)ethynyl!quinuclidin-3-olas a gum, NMR(CDCl₃): 1.18(3H,t), 1.30(2H,d), 1.45(1H,m), 1.65(1H,m),2.02(3H,m), 2.20(1H,m), 2.53(2H,m), 2.87(4H,m), 3.06(1H,d), 3.22(1H,m),3.30(1H,d.d), 3.50(2H,d), 4.07(2H,q), 5.05(2H,m), 5.95(1H,m), 7.02(2H,m)and 7.33(1H,d); m/z 382(M+H).

The compound of formula 2 (Z=OSO₂ CF₃) used as starting material wasprepared as follows.

Triethyl phosphonacetate (5.0 g) was added to a stirred suspension ofsodium hydride (0.95 g; 60% dispersion in oil) in THF (35 ml) at ambienttemperature under an atmosphere of argon. After 1 hour, a solution of4-benzyloxyacetophenone (5.0 g) in tetrahydrofuran (35 ml) was added.The reaction mixture was heated at reflux for 16 hours. The reactionmixture was cooled to ambient temperature and water (200 ml) was added.The aqueous mixture was extracted with ether. The ether phase was washedwith water, brine, dried (MgSO₄) and evaporated. The residue waspurified on silica gel using a 19:1 (v/v) mixture as eluent to giveethyl 3-methyl-3-(4-benzyloxy)phenyl cinnamate (3.44 g) as a colourlesssolid; NMR (CDCl₃): 1.31(3H,t), 2.52(3H,s), 4.20(2H,q), 5.08(2H,s),5.95(1H,m), 6.93(2H,m) and 7.40(7H,m); m/z 297(M+H).

Ethyl 3-(4-benzyloxyphenyl)but-2-enoate (3.4 g) in ethyl acetate (100ml) was hydrogenated over a 10% palladium-on-carbon catalyst (250 mg) atatmospheric pressure/ambient temperature. The catalyst was removed byfiltration and the filtrate evaporated to give an oil. The oil waspurified by chromatography on silica gel using a 4/1 (v/v) mixture ofhexane and ethyl acetate as eluent to give ethyl3-(4-hydroxyphenyl)butanoate (1.51 g) as a pale yellow oil; NMR(CDCl₃):1.20(3H,t), 1.27(3H,d), 2.52(2H,q), 3.22(1H,m), 4.08(2H,q), 4.84(1H,s),6.71(2H,m) and 7.08(2H,m); m/z 208(M). Ethyl3-(4-allyloxyphenyl)butanoate was prepared using the procedue used toprepare ethyl 3-(4-allyloxyphenyl)propionate (see Example 1) but usingethyl 3-(4-hydroxyphenyl)butanoate in place of ethyl3-(4-hydroxyphenyl)propionate; NMR(CDCl₃) 1.17(3H,t), 1.25(3H,d),2.51(2H,m), 3.22(1H,m), 4.05(2H,q), 4.50(2H,m), 5.33(2H,m), 6.06(1H,m),6.82(2H,m) and 7.11(2H,m); m/z 249 (M+H).

Ethyl 3-(3-allyl-4-hydroxyphenyl)butanoate was prepared as for ethyl3-(3-allyl-4-hydroxyphenyl)propionate as in Example 1 but using ethyl3-(4-allyloxyphenyl)butanoate in place of ethyl3-(4-allyloxyphenyl)propionate; microanalysis: found: C, 72.6; H, 7.80%;C₁₅ H₂₀ O₃ requires C, 72.6; H, 8.12%; m/z 249(M+H).

The compound of formula 2 (Z=O.SO₂ CF₃) was prepared as for ethyl3-(3-allyl-4-trifluorosulphonyloxyphenyl)propionate in Example 1 usingethyl 3-(3-allyl-4-hydroxyphenyl)butanoate in place of ethyl3-(3-allyl-4-hydroxyphenyl)propionate. There was thus obtained an oil;NMR(CDCl₃): 1.17(3H,t), 1.41(3H,d), 2.55(2H,m), 3.30(1H,m), 3.46(2H,d),4.08(2H,q), 5.12(2H,m), 5.90(1H,m) and 7.13(3H,m).

EXAMPLE 129

In a similar manner to that described in Example 97, but usingisobutyryl chloride in place of pivaloyl chloride, there was obtained 3-2-(4-dimethylacetyloxymethyl-2-allylphenyl)ethynyl!quinuclidin-3-ol as asolid, m.p. 68° C.; microanalysis, found: C, 75.5; H, 8.0; N, 4.0%; C₂₃H₂₉ NO₃ requires: C, 75.2; H, 8.0; N, 3.8%; NMR (CDCl₃): 1.2 (6H, d),1.4 (1H, m), 1.65 (1H, m), 2.1 (3H, m), 2.6 (1H, m), 2.8 (4H, t), 3.1(1H, d), 3.3 (1H, dd), 3.5 (2H, d), 5.1 (4H, m), 5.9 (1H, m), 7.1 (2H,m) and 7.4 (11H, d), m/z 368 (M+H).

EXAMPLE 130

In a similar manner to that described in Example 97, but using ethylmalonyl chloride in place of pivaloyl chloride, there was obtained 3-2-(4-carbethoxyacetyloxymethyl-2-allylphenyl)ethynyl!quinuclidin-3-ol asan oil, NMR (CDCl₃): 1.2 (3H, t), 1.4 (1H, m), 1.65 (1H, m), 2.1 (3H,m), 2.8 (4H, m), 3.1 (1H, d), 3.3 (1H, dd), 3.4 (2H, s), 3.5 (2H, s),3.5 (2H, d), 4.2 (2H, q), 5.1 (4H, m), 5.9 (1H, m), 7.1 (2H, m) and 7.4(1H, d), m/z 412 (M+H).

EXAMPLE 131

Sodium borohydride (33 mg) was added to a solution of 3-2-(4-(2-dicarbethoxyethylenyl)-2-allylphenyl)ethynyl!quinuclidin-3-ol(306 mg) in ethanol (7 ml) whilst maintaining the temperature at 5° C.The resulting mixture was stirred at 25° C. for 12 hours, filtered, andthe ethanol was then evaporated. The residue was stirred with acetone (5ml) and 1 h aqueous hydrochloric acid (2.75 ml) was then added. Theresulting mixture was stirred at 25° C. for 3 hours and sodium hydrogencarbonate (250 mg) was then added. The mixture was extracted with ethylacetate (3×15 ml). The ethyl acetate extracts were combined, washed withbrine (15 ml), dried (Na₂ SO₄) and evaporated to give a residue whichwas purified by medium pressure column chromatography on alumina(N32-63) using a 49:1 (v/v) mixture of ethyl acetate and methanol aseluent to give 3-2-(4-(2-dicarbethoxyethyl)-2-allylphenyl)ethynyl!quinuclidin-3-ol as asolid, m.p. 89° C.; microanalysis, found: C, 70.8; H, 7.8; N, 3.1%; C₂₆H₃₃ NO₅ requires: C, 71.0; H, 7.6; N, 3.2%; NMR (CDCl₃): 1.2 (6H, t),1.4 (1H, m), 1.65 (1H, m), 2.1 (3H, m), 2.8 (4H, t), 3.0 (1H, d), 3.1(2H, d), 3.3 (1H, dd), 3.4 (2H, d), 3.6 (1H, t), 4.1 (4H, q), 5.1 (2H,m), 5.9 (1H, m), 7.0 (2H, m) and 7.2 (1H, d). m/z 440 (M+H).

EXAMPLE 132

Butyl Lithium in hexane (1.6M, 3.4 ml) was added slowly to a stirredsolution of trimethylsilylacetylene (1.0 g) in tetrahydrofuran (20 ml)at -70° C. under an atmosphere of argon. The reaction mixture wasstirred at -70° C. for a further 60 minutes. A solution of 3-2-(2-formylphenyl)ethynyl!-3-trimethylsilyloxyquinuclidine (1.3 g) intetrahydrofuran (10 ml) was added slowly to the reaction mixture whilstmaintaining the temperature at -70° C. The reaction mixture was allowedto warm to ambient temperature and then stirred for 20 hours. Thereaction mixture was evaporated, potassium carbonate (4 g) and methanol(50 ml) added and the mixture was stirred vigorously at ambienttemperature for 60 minutes. The inorganic salts were removed byfiltration and the filtrate was evaporated to give a residue which wasdissolved in ethyl acetate (150 ml). The solution was extracted with 2Mhydrochloric acid (2×100 ml). The aqueous extracts were combined, washedwith ether (2×200 ml) and then basified to pH 9 by addition of 5N sodiumhydroxide solution. The aqueous mixture was extracted with ethyl acetate(2×100 ml), the ethyl acetate extracts combined, washed with water (100ml), brine (100 ml), dried (MgSO₄) and evaporated. The residue waspurified by column chromatography on alumina (Alumina N 32-63) using agradient of 2:98 to 5:95 (v/v) methanol in ethyl acetate as eluent togive a solid which was recrystallised from a mixture oftetrahydrofuran/hexane to give 3-2-{2-(1-hydroxy-1-ethynylmethyl)phenyl}ethynyl!quinuclidin-3-ol (110mg), m.p. 217° C.; microanalysis; found: C, 74.6; H, 7.2; N, 4.6%, C₁₈H₁₉ NO₂.0.5 H₂ O requires: C, 74.5; H, 6.9; N, 4.8%; NMR: 1.2-1.4 (1H,m), 1.45-1.7 (1H, m), 1.8-2.05 (3H, m), 2.55-2.8 (4H, m), 2.85 (1H, d),3.15 (1H, d), 3.38 (1H, dd), 5.58 (1H, s), 5.6-5.7 (1H, m), 6.08 (1H,d), 7.25-7.46 (3H, m), 7.65 (1H, d), m/z 282 (M+H).

The 3- 2-{2-formylphenyl}ethynyl!-3-trimethylsilyloxy quinuclidine usedas starting material was obtained as follows.

Bis(triphenylphosphine)-palladium(II) chloride (175 mg) and copper(I)iodide (85 mg) were added to a solution of 2-bromobenzaldehyde (2.03 g)and 3-ethynyl-3-trimethylsilyloxyquinuclidine (2.23 g) in dimethylformamide (25 ml) and triethylamine (5 ml) at ambient temperature underan atmosphere of argon. The reaction mixture was stirred at ambienttemperature for 21 hours. The reaction mixture was poured into water(150 ml) and extracted with ethyl acetate (2×100 ml). The ethyl acetateextracts were combined, filtered, washed with water (2×100 ml), brine(100 ml), dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography on alumina (Alumina N 32-63) using a 40:60 (v/v)mixture of ethyl acetate and isohexane as eluent to give 3-2-{2-formylphenyl}ethynyl!-3-trimethylsilyloxyquinuclidine as an oil(2.1 g), NMR: 0.00 (9H, s), 1.1-1.3 (1H, m), 1.35-1.54 (1H, m),1.82-1.90 (1H, m), 2.5 (4H, t), 2.73 (1H, d), 3.07 (1H,d), 7.38-7.48(2H, m), 7.5-7.6 (1H, m), 7.68-7.75 (1H, m), 10.2 (1H, s), m/z 328(M+H).

The 3-ethynyl-3-trimethylsilyloxyquinuclidine used as starting materialwas obtained as follows.

3-Ethynyl-3-hydroxyquinuclidine (1.5 g) and imidazole (1.7 g) werestirred in dimethyl formamide (25 ml). Trimethylsilylchloride (1.35 g)was added slowly to the solution and the mixture was stirred at ambienttemperature for 20 hours. The reaction mixture was poured into water(150 ml) and the aqueous phase extracted with ethyl acetate (2×100 ml).The ethyl acetate extracts were combined, washed with water (2×100 ml),brine (100 ml), dried (MgSO₄) and evaporated to give3-ethynyl-3-trimethylsilyloxyquinuclidine as an oil (1.8 g), NMR: 0.15(9H, s), 1.2-1.38 (1H, m), 1.42-1.6 (1H, m), 1.65-1.9 (3H, m), 2.55-2.7(4H, m), 2.76 (1H, d), 3.02 (1H, d), 3.55 (1H, s), m/z 224 (M+H).

A solution of 3-2-{formylphenyl}ethynyl!-3-trimethylsilyloxyquinuclidine (0.815 g) intetrahydrofuran (5 ml) was added slowly to a stirred solution of vinylmagnesium bromide (1.0M in tetrahydrofuran; 5 ml) in tetrahydrofuran (50ml) at ambient temperature. The reaction mixture was stirred and heatedat reflux for 3 hours. The reaction mixture was evaporated and theresidue dissolved in 2M hydrochloric acid (50 ml). The aqueous phase waswashed with ether (2×100 ml) and then basified to pH 9 by cautiousaddition of solid potassium carbonate. The mixture was extracted withethyl acetate (2×100 ml). The ethyl acetate extracts were combined,washed with water (100 ml), brine (100 ml), dried (MgSO₄) andevaporated. The residue was purified by column chromatography on alumina(Alumina N 32-63) using a 5:95 (v/v) mixture of methanol in ethylacetate as eluent to give a solid which was recrystallised fromacetonitrile to give 3-2-{-(1-hydroxy-1-ethenylmethyl)phenyl}ethynyl-3-hydroxy quinuclidine(117 mg), m.p. 148-149.5° C.; microanalysis, found: C, 75.9; H, 7.5; N,4.9%; C₁₈ H₂₁ NO₂ requires: C, 76.3; H, 7.5; N, 4.9%; NMR: 1.2-1.4 (1H,m), 1.42-1.68 (1H, m), 1.7-2.0 (3H, m), 2.62 (4H, t), 2.85 (1H, d), 3.07(1H, d), 4.95-5.07 (1H, m), 5.16-5.3 (1H, m), 5.45-5.56 (2H, m), 5.58(1H, s), 5.86-6.08 (1H, m), 7.17-7.27 (1H, m), 7.3-7.4 (2H, m),7.46-7.52 (1H, m), m/z 284 (M+H).

EXAMPLE 133

The β-ketoester prepared in Example 51 (0.22 g) was converted to itshydrochloride salt by dissolving in ethanol, and acidifying theresulting solution by adding ethanolic hydrogen chloride until thesolution was pH 1. The solvent was removed immediately and the residuewas dissolved in anhydrous dimethylformamide (5 ml) whilst under anatmosphere of argon. Sodium borohydride (0.044 g) was added to themixture and the mixture was stirred for 1 day. An excess of sodiumborohydride was added to the reaction mixture followed by anhydrousethanol (5 ml). The reaction mixture was stirred overnight.

The reaction mixture was cooled with an ice-bath and quenched by carefuladdition of saturated ammonium chloride solution, whilst under anatmosphere of argon. The aqueous mixture was extracted with ethylacetate (3×50 ml). The ethyl acetate extracts were combined, washed withbrine (50 ml), dried (MgSO₄) and evaporated to give a colourless oil(0.2 g); m/z 354 (M-H). This oil was dissolved in acetone (5 ml) andtreated with ethanolic HCl, until the pH>1. The mixture was stirred fora few hours at room temperature. The solvent was removed by evaporationand the residue was partitioned between saturated sodium carbonatesolution (20 ml) and ethyl acetate (20 ml). The aqueous layer wasfurther extracted with ethyl acetate (2×20cm³). The ethyl acetateextracts were combined, washed with brine, dried (MgSO₄) and evaporatedto produce a crude oil. The oil was purified by chromatography on silicagel (Varian Bond Elut S1 silica gel) using a 80:20:3 (v/v/v) mixture ofethyl acetate/ethanol/triethylamine as eluent to give 3-2-(2-allyl-4-(1,2-dihydroxyethyl)phenyl)ethynyl!quinuclidin-3-ol as agum (0.05 g); m/z 342(M+H).

EXAMPLE 134

The procedure described in Example 97 was repeated using benzyl alchol(0.4 g) and ethyl chloroformate as starting materials to give 3-2-(2-allyl-4-ethoxycarbonyloxymethylphenyl)ethynyl (0.04 g);m/z370(M+H).

EXAMPLE 135

A solution of hydrogen chloride dissolved in ethanol was added to asolution of 3-2-(2-allyl-4-(ethoxycarbonylethylcarbonyl)phenyl)ethynyl!quinuclidin-3-ol(0.36 g) in ethanol (5 ml) to give a pH of 1. The mixture was evaporatedand the residue was dissolved in ethanol (5 ml). Sodium borohydride (0.3g) was added over a period of 4 hours. The reaction mixture was stirredovernight. The mixture was acidified with 2M aqueous hydrochloric acid.The mixture was filtered and the filtrate was evaporated. The residuewas treated with acetone/ethereal hydrogen chloride mixture and thenevaporated.

The residue was purified by chromatography on silica gel (Varian BondElut S1 silica gel) using an 80:20:3 mixture of ethylacetate/ethanol/triethylamine as eluent to give 3-2-(2-allyl-4-(1,4-dihydroxybutyl)phenyl)ethynyl!quinuclidin-3-ol (24 mg)as a gum; m/z 355(M+H).

EXAMPLE 136

The procedure described in Example 1 was repeated using1-(methoxymethyl)-2-(trifluoromethylsulphonyloxy)benzene in place ofethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate. Therewas thus obtained 3- 2-(2-methoxymethyphenyl)ethynyl!quinuclidin-3-ol asan oil; NMR(CDCl₃): 1.2-1.4(1H,m), 1.5-1.7(1H,m), 1.8-2.02(3H,m),2.6-2.8(4H,m), 2.82-2.92(1H,d), 3.05-3.15(1H,d), 3.4(3H,s), 4.62(2H,s)and 7.4(4H,m).

EXAMPLE 137

Illustrative pharmaceutical dosage forms suitable for presenting thecompounds of the invention for therapeutic or prophylactic use includethe following tablet and capsule formulations, which may be obtained byconventional procedures well known in the art of pharmacy and aresuitable for therapeutic or prophylactic use in humans:

    ______________________________________    (a) Tablet I            mg/tablet    ______________________________________    Compound Z*             1.0    Lactose Ph. Eur.        93.25    Croscarmellose sodium   4.0    Maize starch paste (5% w/v aqueous paste)                            0.75    Magnesium stearate      1.0    ______________________________________    (b) Tablet II           mg/tablet    ______________________________________    Compound Z*             50    Lactose Ph. Eur         223.75    Croscarmellose sodium   6.0    Maize starch            15.0    Polyvinylpyrrolidone (5% w/v aqueous paste)                            2.25    Magnesium stearate      3.0    ______________________________________    (c) Tablet III          mg/tablet    ______________________________________    compound Z*             100    Lactose Ph. Eur.        182.75    Croscarmellose sodium   12.0    Maize starch paste (5% w/v aqueous paste)                            2.25    Magnesium stearate      3.0    ______________________________________    (d) Capsule             mg/capsule    ______________________________________    Compound Z*             10    Lactose Ph. Eur.        488.5    Magnesium stearate      1.5    ______________________________________     Note     *The active ingredient Compound Z is a compound of formula I, or a salt     thereof, for example a compound of formula I described in any of the     preceding Examples.

The tablet compostions (a)-(c) may be enteric coated by conventionalmeans, for example, with cellulose acetate phthalate ##STR2## 1. CBr₄/PPh₃ /Zn, CH₂ Cl₂, ROOM TEMPERATURE 2. (a) n.BuLi (2 equiv), THF, -60°C., ARGON ATMOSPHERE (b) H₂ O

3. Br₂ /H₂ O

4. t. BuOK, t-BuOH, REFLUX ##STR3## 1. H₂ /Pd. --C.tbd.CO₃, EtOH 2. Ph₃⁺ PCH₃ Br⁻, KOBu^(t), THF

3. PHTHALIC ANHYDRIDE, BENZENE SULPHONIC ACID. 280° C. ##STR4## 1. H₂/Pd-CaCO₃, ETOH 2. (a) H₂ C═CHMgBr, THF, 20-25° C. (b) NH₄ Cl solution##STR5## 1. Me₃ Si--C.tbd.C--Li, THF, -70° C. to -75° C., ARGONATMOSPHERE

2. K₂ CO₃, MeOH, 20-25° C. ##STR6##

We claim:
 1. A compound of formula I, or a pharmaccutically acceptablesalt thereof, wherein:R¹ is hydrogen or hydroxy; R² is hydrogen; or R¹and R² are joined together so that CR¹ -CR² is a double bond; X isselected from --CH₂ CH₂ --, --CH═CH--, --C.tbd.C--, --CH₂ O--, --OCH₂--, --CH₂ NH--, --NHCH₂ --, --CH₂ CO--, --COCH₂ --, --CH₂ S(O)_(n) --and --S(O)_(n) --CH₂ -- (wherein n is 0,1 or 2); Ar is phenyl whichbears one or more substituents independently selected from the groups(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di- (1-6C)alkyl!amino,carbamoyl, (1-6C)alkylcarbamoyl, di- (1-6C)alkyl!carbamoyl,(1-6C)alkanoyl, (1-6C)alkanoyl oxime, O-(1-6C)alkyl ethers of a(1-6C)alkanoyl oxime, (1-6C)alkylthio, (1-6C)alkylsulphinyl and(1-6C)alkylsulphonyl, which substituent is itself substituted by one ormore groups selected from (1-6C)alkoxycarbonyl, (1-6C)alkanoyl,(1-6C)alkanoyl oxime, O-(1-6C)alkyl ethers of a (1-6C)alkanoyl oxime,(1-6C)alkanoylamino, (1-6C)alkanoyloxy, (1-6C)alkanoyloxy(1-6C)alkyl,carbomoyl, N-(1-6C)alkylcarboamoyl, N,N-di (1-6C)alkylcarbamoyl, amino,(1-6C)alkylamino, di- (1-6C)alkyl!amino, (1-6C)alkoxy, (2-6C)alkenyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,halogeno(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, cyano, nitro andcarboxy; and wherein Ar may optionally bear one or more substituentsindependently selected from halogeno, hydroxy, amino, nitro, cyano,carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-6C)alkylamino, di- (1-6C)alkyl!aminoN-(1-6C)alkylcarboamoyl, di-N,N- (l1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl, (1-6C)alkanoyl oxime, andO-(1-6C)alkyl ethers of a (1-6C)alkanoyl oxime, provided that whenX is--OCH₂ --, --NHCH₂ -- or --S(O)_(n) CH₂ -- (wherein n is 0,1 or 2), thenR¹ is not hydroxy.
 2. A compound of formula I, or a pharmaceuticallyacceptable salt thereof, ##STR7## wherein: R¹ is hydroxy;R² is hydrogen;X is selected from --CH₂ CH₂ --, --CH═CH--, --C.tbd.C--, --CH₂ O--,--CH₂ NH--, --CH₂ CO--, --COCH₂ --, and --CH₂ S(O)_(n) -- (wherein n is0,1 or 2); Ar is phenyl which bears one or more substituentsindependently selected from the groups (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)akoxy, (1-6C)alkoxycarbonyl,(1-6C)alkoxyearbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl,(1-6C)alkylamino, di- (1-6C)alkyl!amino, carbamoyl,(1-6C)alkylcarbamoyl, di- (1-6C)alkyl!carbamoyl, (1-6C)alkanoyl,(1-6C)alkanoyl oxime, O-(1-6C)alkyl ethers of a (1-6C)alkanoyl oxime,(1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonly, whichsubstituent is itself substituted by one or more groups seected from(1-6C)alkoxycarbonyl, (1-6C)alkanoyl, (1-6C)alkanoyl oxime,O-(1-6C)alkyl ethers of a (1-6C)alkanoyl oxime, (1-6C)alkanoylamino,(1-6C)alkanoyloxy, (1-6C)alkanoyloxy(1-6C)alkyl, carbamoyl,N-(1-6C)alkylcarbamoyl, N,N-di (1-6C)alkylcarbamoyl, amino,(1-6C)alkylamino, di- (1-6C)alkyl!amino, (1-6C)alkoxy, (2-6C)alkenyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,halogeno(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, cyano, nitro, hydroxyand carboxy; and wherein Ar may optionally bear one or more substituentsindependently selected from halogeno, hydroxy, amino, nitro, cyano,carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-6C)alkylamino, di- (1-6C)alkyl!aminoN-(1-6C)alkylcarbomoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl, (1-6C)alkanoyl oxime, andO-(1-6C)alkyl ethers of a (1-6C)alkanoyl oxime.
 3. A compound of formulaI, or a pharmaceutically acceptable salt thereof, ##STR8## wherein; R¹is hydrogen or hydroxy;R² is hydrogen; or R¹ and R² are joined togetherso that CR¹ -CR² is a double bond; X is selected from --CH₂ CH₂ --,--CH═CH--, --C.tbd.C--, --CH₂ O--, --OCH₂ --, --CH₂ NH--, --NHCH₂ --,--CH₂ CO--, --COCH₂ --, --CH₂ S(O)_(n) -- and --S(O)_(n) CH₂ -- (whereinn is 0,1 or 2); Ar is phenyl which bears one or more substituentsindependently selected from the groups (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino,di- (1-6C)alkyl!amino, (1-6C)alkylthio, (1-6C)alkylsulphinyl and(1-6C)alkylsulphonyl, which substituent is itself substituted by one orsore groups selected from (1-6C)alkoxycarbonyl, (1-6C)alkanoyl,(1-6C)alkanoylamino, (1-6C)alkanoyloxy, N-(1-6C)alkylcarbamoyl, N,N-di(1-6C)alkylcarbamoyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, cyanoand nitro; and wherein Ar may optionally bear one or more substituentsindependently selected from halogeno, hydroxy, amino, nitro, cyano,carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-6C)alkylamino, di- (1-6C)alkyl!aminoN-(1-6C)alkylcarbarmoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl, (1-6C)alkanoyl oxime, andO-(1-6C)alkyl ethers of a (1-6C)alkanoyl oxime; provided that when X is--OCH₂, --NHCH₂ -- or --S(O)_(n) CH₂ -- (wherein n is 0,1 or 2), then R¹is not hydroxy.
 4. A compound of formula I, or a pharmaccuticallyacceptable salt thereof, ##STR9## wherein: R¹ is hydroxy;R² is hydrogen;X is selected from --CH₂ CH₂ --, --CH═CH--, --C.tbd.C--, --CH₂ O--,--CH₂ NH--, --CH₂ CO--, --COCH₂ -- and --CH₂ S(O)_(n) -- (wherein n is0,1 or 2); Ar is phenyl which bears one or more substituentsindependently selected from the groups (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino,di- (1-6C)alkyl!amino, (1-6C)alkylthio, (1-6C)alkylsulphinyl and(1-6C)alkylsulphonyl, which substituent is itself substituted by one ormore groups selected from (1-6C)alkoxycarbonyl, (1-6C)alkanoyl,(1-6C)alkanoylamnino, (1-6C)alkanoyloxy, N-(1-6C)alkylcarbamoyl, N,N-di(1-6C)alkylcarbamoyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, cyano,nitro, and hydroxy; and wherein Ar may optionally bear one or moresubstituents independently selected from halogeno, hydroxy, amino,nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di- (1-6C)alkyl!aminoN-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl, (1-6C)alkanoyl oxime, andO-(1-6C)alkyl ethers of a (1-6C)alkanoyl oxime.
 5. A compound as claimedin claim 1 wherein Ar is phenyl which bears one or more substituentsselected from (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylthio(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxy(1 6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkanoyl(1-6C)alkyl,(1-6C)alkoxyoarbonyl(1-6C)alkanoyl and carboxy(1-6C)alkyl; andoptionally bears one or more further substituents selected fromhalogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-(1-6C)alkyl!amino N-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl, (1-6C)alkanoyl oxime, andO-(1-6C)alkyl ethers of a (1-6C)alkanoyl oxime.
 6. A compound as claimedin claim 2 wherein Ar is phenyl which bears one or more substituentsselected from (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylthio(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxycarbonyl(1-6C)alkoxy, hydroxy(1-6C)alkyl,(1-6C)alkanoyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkanoyl andcarboxy(1-6C)alkyl; and optionally bears one or more furthersubstituents selected from halogeno, hydroxy, amino, nitro, cyano,carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-6C)alkylamino, di (1-6C)alkyl!aminoN-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino(1-4C)alkylenedioxy, (1-6C)alkanoyl, (1-6C)alkanoyl oxime, andO-(1-6C)alkyl ethers of a (1-6C)alkanoyl oxime.
 7. A compound as claimedin claim 2 wherein R¹ is hydroxy, R² is hydrogen, X is selected from--CH₂ CH₂ --, --CH═CH--, --C.tbd.C-- and --CH₂ O--; Ar is phenyl whichbears one or more substituents independently selected from(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl,di-(1-6C)alkoxy, (1-6C)alkoxycarbonyl(2-6C)alkenyl,(1-6C)alkoxycarbonyl(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxycarbonyl, (1-6C)alkylthio(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkylcarbamoyl,(1-6C)alkoxy(1-6C)alkylcarbamoyl, (1-6C)alkanoyloxy(1-6C)alkyl,cyano(1-6C)alkoxy, carboxy(1-6C)alkyl, cyano(1-6C)alkyl,hydroxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkanoyl,(1-6C)alkylthio(1-6C)alkyl, (2-6C)alkenyl(1-6C)alkoxy(1-6C)alkyl, and(1-6C)alkanoyl(1-6C)alkyl, (1-6C)alkanoyl(1-6C)alkyl oxime andO-(1-6C)alkyl ethers of (1-6C)alkanoyl(1-6C)alkyl oxime; and wherein Armay optionally bear one or more substituents independently selected fromhalogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-(1-6C)alkyl!amino N-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl, (1-6C)alkanoyl oxime andO-(1-6C)alkyl ethers of (1-6C)alkanoyl oxime.
 8. A compound as claimedin claim 2 wherein R¹ is hydroxy, R² is hydrogen, X is --C.tbd.C--, Aris phenyl which bears a substituent selected frommethoxyethoxycarbonylethyl, methoxypropyl, ethoxycarbonylethyl,methoxycarbonylethyl, methoxycarbonylpropyl, methoxycarbonylbutyl,iso-butoxycarbonylethyl, hexyloxycarbonylethyl, methoxycarbonylpropyl,methoxycarbonylpentyl, methoxycarbonylmethoxy, methoxyethoxy,methoxyethoxymethyl, methoxyethoxyethyl, carboxyethyl, carboxypropyl,hydroxymethyl, ethanoylethyl, ethoxycarbonylethanoyl,ethoxycarbonylpropanoyl; and optionally one or more substituentsselected from (1-6C)alkyl, (2-6C)alkenyl, halogeno, (1-6C)alkoxy and(1-6C)alkanoyl.
 9. A compound as claimed in claim 1 wherein Ar is phenylwhich bears a substituent selected from (1-6C)alkoxycarbonyl(1-6C)alkyland carboxy(1-6C)alkyl, and which optionally bears one or moresubstituents selected from the optional substituents defined in claim 1.10. A compound as claimed in claim 9 wherein R¹ is hydroxy, R² ishydrogen, X is --C.tbd.C--, Ar is phenyl which bears a substituentselected from (1-6C)alkoxycarbonyl(1-6C)alkyl and carboxy(1-6C)alkyl,and optionally bears a (2-6C)alkenyl group.
 11. A compound as claimed inclaim 2 wherein R¹ is hydroxy, R² is hydrogen, X is selected from --CH₂CH₂ --, --CH═CH--, --C.tbd.C-- and --CH₂ O--; Ar is phenyl which bearsone or more substituents independently selected from(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl and(1-6C)alkoxy(1-6C)alkoxycarbonyl; and Ar optionally bears one or morefurther substituents selected from halogeno, hydroxy, amino, nitro,cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-6C)alkylamino, di- (1-6C)alkyl!aminoN-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino,(1-4C)alkylenedioxy, (1-6C)alkanoyl, (1-6C)alkanoyl oxime andO-(1-6C)alkyl ethers of (1-6C)alkanoyl oxime.
 12. A compound as claimedin any one of claims 1 or 2 wherein X is selected from --C.tbd.C--,--CH₂ CH₂ --, --CH₂ O-- and --CH═CH--.
 13. A compound as claimed inclaim 2 wherein X is --C.tbd.C--.
 14. A compound selected from:3-2-(2-allyl-4-(2-ethoxycarbonylethyl)phenyl)ethynyl!quinuclidin-3-ol; 3-2-(2-allyl-4-(2-methoxycarbonylethyl)phenyl)ethynyl!quinuclidin-3-ol; 3-2-(2-allyl-4-(3-methoxycarbonylpropyl)phenyl)ethynyl!quinuclidin-3-ol;3- 2-(2-allyl-4-(4-methoxycarbonylbutyl)phenyl)ethynyl!quinuclidin-3-ol;3-2-(2-allyl-4-(2-iso-butoxycarbonylethyl)phenyl)ethynyl!quinuclidin-3-ol;3-2-(2-allyl-4-(2-(2-methoxyethoxycarbonyl)ethyl)phenyl)ethynyl!quinuclidin-3-ol;3- 2-(2-allyl-4-(3-methoxypropyl)phenyl)ethynyl!quinuclidin-3-ol; 3-2-(2-allyl-4-(2-hexyloxycarbonylethyl) phenyl)ethynyl! quinuclidin-3-ol.3-2-(2-allyl-4-(2-methoxycarbonyl-2-methylethyl)phenyl)ethynyl!quinuclidin-3-ol;3- 2-(2-allyl-4-(2-carboxyethyl)phenyl)ethynyl!quinuclidin-3-ol; 3-2-(2-allyl-4-(5-methoxycarbonylpentyl)phenyl)ethynyl!quinuclidin-3-ol;and 3- 2-(2-allyl-4-(2-carboxypropyl)phenyl)ethynyl!quinuclidin-3-ol;andpharmaceutically acceptable salts thereof.
 15. A process for preparing acompound of formula I or a pharmaceutically acceptable salt thereof, asclaimed in claim 1 or 2, wherein Ar, R¹ and R² are defined therein,which process comprises:(a) for these compounds of formula I in which R¹and R² are both hydrogen, reducing a compound of formula I in which R¹and R² are joined together so that CR¹ -CR² is a double bond; (b) forcompounds of formula I in which R¹ and R² are joined together so thatCR¹ -CR² is a double bond, dehydrating a compound of formula I in whichR¹ is hydroxy and R² is hydrogen; (c) for compounds of formula I inwhich R¹ and R² are joined together so that CR¹ -CR² is a double bond,treating a compound of formula II ##STR10## in which Z is a leavinggroup with a base; (d) for those compounds of formula I in which X is--CH₂ CO--, reacting an organometallic compound of formula III:

    Ar--M                                                      (III)

in which M is a metal atom or a derivative thereof, with a compound offormula IV: ##STR11## e) for those compounds of formula I in which X is--CH₂ --NH-- or --NHCH₂ --, reducing a compound of formula I in which Xis --CH═N-- or --N═CH--; f) for those compounds of formula I in which Xis --CH₂ NH--, --CH₂ O--, --CH₂ S--, R¹ is hydroxy and R² is hydrogen,reacting a compound of formula IX:

    Ar--Z                                                      (IM)

in which Z is --NH₂, --OH or SH with a compound of formula X: ##STR12##g) for compounds of formula I in which X is --CH═CH--, reacting thereaction product of a compound of formula ArCH₂ -halogen withtriphenylphosphine with a compound of formula V: ##STR13## in thepresence of a base; h) for those compounds of formula I in which X is--CH₂ CH₂ --, reducing a compound of formula I in which X is --CH═CH--or in which X is --C.tbd.C--; i) for compounds of formula I in which Xis --COCH₂ --, reacting a compound of formula XII:

    Ar--CH.sub.2 M                                             (XII)

in which M is a metal atom or a derivative thereof, with a compound offormula XIII: ##STR14## j) for those compounds of formula I in which Xis --CH₂ O-- or --CH₂ S--, reacting a compound of formula XIV

    ArCH.sub.2 Z.sup.1                                         (XIV)

with a compound of formula XV ##STR15## in which Z¹ is a leaving groupand Z² is --YM, or Z¹ is --YM and Z² is a leaving group, and wherein Yis oxygen or sulphur and M is a metal atom; k) for those compounds offormula I in which X is --OCH₂ -- or --SCH₂ -- and R¹ and R² are bothhydrogen, reacting a compound of formula XVI:

    ArYH                                                       (XVI)

in which Y is oxygen or sulphur as appropriate with a compound offormula XVII ##STR16## in which Z is a leaving group; l) for compoundsof formula I in which X is --OCH₂ --, --SCH₂ --, --CH2O--, or --CH₂ S--,deprotecting a compound of formula XVIII ##STR17## in which Q is aprotecting group; m) for those compounds of formula I in which X is--C.tbd.C--, reacting a compound of formula I in which X is --CH═CH--with a halogen, followed by treatment with a base; n) for thosecompounds of formula I in which R¹ is hydroxy, R² is hydrogen and X is--C.tbd.C--, reacting a compound of formula XIX:

    Ar--C.tbd.CM                                               (XIM)

in which M is a metal atom, with quinuclidin-3-one; o) for thosecompounds in which R¹ and R² are hydrogen and X is --C.tbd.C--, reactinga compound of formula XIX

    Ar--C.tbd.CM                                               (XIM)

in which M is a metal atom with a compound of formula XV ##STR18## inwhich Z is a leaving group; p) for those compounds in which X is--C.tbd.C-- and R¹ is hydrogen or hydroxy and R² is hydrogen, reacting acompound of formula XX: ##STR19## with a compound of formula IX:

    Ar--Z                                                      (IX)

in which Z is a leaving group in the presence of a catalyst; q) forthose compounds in which X is --C═C-- and R¹ is hydrogen or hydroxy andR² is hydrogen, reacting a compound of formula XXI: ##STR20## with acompound of formula IX:

    Ar--Z                                                      (IX)

in which Z is a leacing group in the presence of a catalyst; r) forthose compounds in which X is --CH═CH--, reducing a compound of formulaI in which X is --C.tbd.C--; s) for those compounds of formula I inwhich X is --CH═CH--, reacting a compound of formula XXII: ##STR21## inwhich L is a (1-6)alkyl with a compound of formula IX:

    Ar--Z                                                      (IX)

in which Z is a leacing group in the presence of a catalyst; andwhereafter, when a pharmaceutically-acceptable salt is required,reacting the compound of formula I with an acid which affords apysiologically acceptable anion or a base which affords a pysiologicallyacceptable cation.
 16. A pharmaceutical composition which comprises acompound of formula I, or a pharmaceutically acceptable salt thereof, asclaimed in claim 1 or 2 together with, or in admixture with, apharmaceutically acceptable diluent or carrier.
 17. A compound offormula I, or a pharmaceutically acceptable salt thereof, ##STR22##wherein: R¹ is hydrogen or hydroxy;R² is hydrogen; or R¹ and R² arejoined together so that CR¹ -CR² is a double bond; X is selected from--CH₂ CH₂ --, --CH═CH--, --C.tbd.C--, --CH₂ O--, --OCH₂ --, --CH₂ NH--,--NHCH₂ --, --CH₂ CO--, --COCH₂ --, --CH₂ S(O)_(n) -- and --S(O)_(n) CH₂-- (wherein n is 0,1 or 2); Ar is phenyl which bears one or moresubstituents independently selected from(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-(1-6C)alkoxy(1-6C)alkyl! (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxycarbonyl,di- (1-6C)alkoxy! (1-6C)alkyl, (1-6C)alkylamino(1-6C)alkyl, di-(1-6C)alkyl!amino(1-6C)alkyl, (1-6C)alkylcarbonylamino(1-6C)alkyl,(3-6C)cycloalkyl(1-6C)alkoxy, (2-6C)alkenyloxy(1-6C)alkyl,carbamoyl(1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl, N,N-di-(1-6C)alkyl!carbamoyl(1-6C)alkyl; (1-6C)alkoxycarbonyl(2-6C)alkenyl,(1-6C)alkoxycarbonyl(2-6C)alkynyl, cyano(1-6C)alkoxy,cyano(1-6C)alkoxy(1-6C)alkyl, nitro(1-6C)alkoxy,nitro(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkylthio,(1-6C)alkoxycarbonyl(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkylthio(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl,(1-6C)alkoxycarbonyl(1-6C)alkylcarbamoyl,(1-6C)alkoxy(1-6C)-alkylcarbamoyl, (1-6C)alkanoyloxy(1-6C)alkyl,cyano(1-6C)alkyl, carboxy(1-6C)alkyl, hydroxy(1-6C)alkyl(1-6C)alkylamino(1-6C)alkyl, di- (1-6C)alkyl!amino(1-6C)alkyl,(1-6C)alkylamino(1-6C)alkoxycarbonyl(1-6C)alkyl, di-(1-6C)alkyl!amino(1-6C)alkoxycarbonyl(1-6C)alkyl,(1-6C)alkylcarbamoyl(1-6C)alkoxycarbonyl, di-(1-6C)alkyl!carbamoyl(1-6C)alkoxycarbonyl,carbamoyl(1-6C)alkoxycarbonyl,(1-6C)alkoxycarbonyl(1-6C)alkoxy(1-6C)alkyl, di-(1-6C)alkyl!amino(1-6C)alkoxycarbonyl,(1-6C)alkoxycarbonyl(1-6C)alkanoyl,(1-6C)alkoxy(1-6C)alkoxy(1-6C)alkanoyl, (1-6C)alkylthio(1-6C)alkyl,(2-6C)alkenyl(1-6C)alkoxy(1-6C)alkyl,(2-6C)alkynyl(1-6C)alkoxy(1-6C)alkyl,halogeno(1-6C)alkyl(1-6C)alkoxycarbonyl, di- (1-6C)alkoxycarbonyl!alkyl,(1-6C)alkoxycarbonyl(1-6C)alkanoyloxy(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkanoyloxy(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl, hydroxy(1-6C)alkoxy,di-hydroxy(1-6C)alkyl, hydroxy(2-6C)alkenyl, hydoxy(2-6C)alkynyl,(1-6C)alkanoyl(1-6C)alkyl, (1-6C)alkanoyl (1-6C)alkyl oxime andO-(1-6C)alkyl ethers of (1-6C)alkanoyl(1-6C)alkyl oxime; and, inaddition, optionally bears one or more substituents independentlyselected from halogeno, hydroxy, amino, nitro, cyano, carboxy,carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di- (1-6C)alkyl!amino N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl,(1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl (1-6C)alkanoyloxime and O-(1-6C)alkyl ethers of (1-6C)alkanoyl oxime;provided thatwhen X is --OCH₂ --, --NHCH₂ -- or --S(O)_(n) CH₂ -- (wherein n is 0,1or 2), then R¹ is not hydroxy.
 18. A compound as claimed in claim 3 or4, respectively wherein Ar is phenyl which bears a substituent selectedfrom (1-6C)alkoxycarbonyl(1-6C)alkyl and carboxy(1-6C)alkyl, and whichoptionally bears one or more substituents selected from the optionalsubstituents defined in claim 3 or
 4. 19. A compound as claimed in claim17 wherein R¹ is hydroxy, R² is hydrogen, X is --C.tbd.C--, Ar is phenylwhich bears a substituent selected from (1-6C)alkoxycarbonyl(1-6C)alkyland carboxy(1-6C)alkyl, and optionally bears a (2-6C)alkenyl group. 20.A pharmaceutical composition which comprises a compound of formula I, ora pharmaceutically acceptable salt thereof, as claimed in claim 3 or 4together with, or in admixture with, a pharmaceutically acceptablediluent or carrier.